VP-R-2026-005

LDLR c.1381G>T

Familial hypercholesterolaemia

Needs reviewHigh

Your DNA didn’t change. Science did. AI assists. Clinicians decide.

Classification change

2022 · On file

Uncertain significance

Reported 11 Oct 2022

Science evolves

Today · ClinVar

Likely pathogenic

ClinVar last evaluated 23 Feb 2024 · Reviewed by expert panel

The DNA has not changed. Only the interpretation has.LDLR c.1381G>T (p.Gly461Cys) · identical in both

Classification drift

Variant

Gene: LDLR
HGVS (coding): c.1381G>T
Protein: p.Gly461Cys
ClinVar: VCV000183113
dbSNP: rs193922568
Panel: Lipid disorders panel
Molecular consequence: missense variant

How the interpretation changed

LDLR c.1381G>T. The DNA is unchanged. The evidence around it is not.

2022Genetic test performedFirst record on file carrying LDLR c.1381G>T.
2022Reported as uncertain significanceMissense change in the EGF-precursor homology domain. Reported as uncertain; segregation data not available.
2024Submissions accumulated10 independent submissions now contribute to the classification.
2024Classification now likely pathogenicLast evaluated 23 Feb 2024 · Reviewed by expert panel.
TodayVariantPulse identified the affected records2 historical records carry this variant and were flagged for clinical review.

Evidence summary draft

AI draft · clinician must review

Evidence summary

Decision support

Since the 2022 report, the consensus for LDLR c.1381G>T has moved from uncertain significance to likely pathogenic. That reading rests on 10 submissions at strong review confidence, reviewed by expert panel. That crosses the clinically actionable boundary, so management guidance issued on the original interpretation may no longer be the right guidance. 2 records on file carry this variant and have not yet been reassessed.

Composed from the structured fields of the records cited on this page. Requires clinical verification before it informs any decision.

Patient impact

The changed variant and every historical record that carries it. Select a record to see its detail.

Synthetic demonstration data

Changed variant

LDLR

c.1381G>T

VUSLikely pathogenic

VP-10543

Not reviewed

35-44 · Lipid Clinic

Synthetic ID: VP-10543
Test date: 11 Oct 2022
Original classification: Uncertain significancereported 11 Oct 2022
Current evidence: Likely pathogenicClinVar, evaluated 23 Feb 2024
Clinical owner: Dr. H. Nassar
Review status: Not reviewed

Open record

Evidence by source

Each source is shown as it reports itself. VariantPulse does not merge them into a single verdict.

Source	Classification	Review level	Last updated	Strength
ClinVar10 submissions on record.	Likely pathogenic	Reviewed by expert panel	23 Feb 2024	Strong3 of 4 review criteria met	VCV000183113
Population frequencyHighest reported allele frequency carried on the source record.	1.00e-5	The Genome Aggregation Database (gnomAD)	23 Feb 2024	Reference observation
LiteraturePublications linked to this variant record.	8 indexed publications	PubMed index	Latest 2022	Supporting context
Regional Evidence IndexModelled regional aggregation maintained inside this workspace	Likely pathogenic	0 regional observations	27 Jan 2026	Cohort 3,042
This institutionThe interpretation issued to the patient at the time of testing.	Uncertain significance	Internal report	11 Oct 2022	On record

Cited publications

ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). · Genet Med 2022 · PMID 35802134
Diagnosis of familial hypercholesterolemia in a large cohort of Italian genotyped hypercholesterolemic patients. · Atherosclerosis 2022 · PMID 35339733
Low Detection Rates of Genetic FH in Cohort of Patients With Severe Hypercholesterolemia in the United Arabic Emirates. · Front Genet 2021 · PMID 35047021
ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). · Genet Med 2021 · PMID 34012068
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. · Genet Med 2017 · PMID 28492532
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. · Genet Med 2017 · PMID 27854360
Genetic causes of monogenic familial hypercholesterolemia in the Greek population: Lessons, mistakes, and the way forward. · J Clin Lipidol 2016 · PMID 27578104
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. · Genet Med 2015 · PMID 25741868

Global and regional evidence

Sources agree

Global · ClinVar

Likely pathogenic

reviewed by expert panel · Last evaluated 23 Feb 2024

Regional · Regional Evidence Index

Likely pathogenic

0 observations in 3,042 · updated 27 Jan 2026

Sources consistent

Both lanes fall in the same clinical band.

Both sources place this variant in the same band.

Global

Likely pathogenic

Submissions: 10
Review status: Reviewed by expert panel
Last evaluated: 23 Feb 2024
Reference frequency: 1.00e-5

Read from ClinVar, which aggregates submissions dominated by European-ancestry cohorts.

Regional

Likely pathogenic

Observations: 0
Cohort size: 3,042
Last updated: 27 Jan 2026
Regional frequency: 0.00e+0

Modelled regional aggregation maintained inside this workspace.

VariantPulse analysis

Both sources place this variant in the same band, so there is no divergence to resolve. Consistent with the global expert-panel reading. The familial hypercholesterolaemia mutation spectrum in Arab countries differs from European cohorts, which is why regional follow-up of LDLR results matters.

Spectrum of mutations of familial hypercholesterolemia in the 22 Arab countries. · Atherosclerosis 2018 · PMID 30415195

How VariantPulse reached this resultEight steps, each one inspectable

1Historical record retrievedLDLR c.1381G>T reported as Uncertain significance on 2022-10-11.
2Variant normalisedResolved to ClinVar VCV000183113 (rs193922568) and keyed as LDLR:c.1381G>T.
3Current evidence retrievedRead live from ClinVar: Likely pathogenic, 10 submissions, reviewed by expert panel.
4Classification difference detectedRecorded interpretation normalised to Uncertain significance. Current interpretation normalised to Likely pathogenic. The interpretation crossed into the clinically actionable band, so records carrying it may need review.
5Regional sources comparedRegional index asserts Likely pathogenic, consistent with the global reading.
6Impacted records identified12,482 findings checked; 2 carry this variant.
7Evidence brief generatedComposed from the structured fields of the cited records above.
8Human review requestedVariantPulse does not change any record. A clinician decides what happens next.

Review priority

A triage signal for the queue. Not a clinical risk score, and not a statement about any individual.

+60Moved into the actionable bandUncertain significance to Likely pathogenic.
+102 records on fileHistorical results carrying this variant that a reviewer would reassess.
+10High review confidenceThe current classification carries expert-panel or guideline review.

Ordering score80

Case trail

Every review action on this case, with who took it and when.

No review actions on this case yet.

Recommendation

Reassess 2 records against the current interpretation and decide whether the reporting clinician should be notified. Final interpretation remains with the clinical team.

Review actions

Each action is recorded in the audit trail. None changes a classification or a diagnosis.

Assign reviewer

Clinician note

Decision

A decision needs a clinician note of at least 10 characters. It records the outcome of the review; it does not write to any patient record or issue a diagnosis.

Case detail

Case: VP-R-2026-005
Raised: just now
Assigned: Unassigned
Evidence source: ClinVar · Evidence monitor live
Records impacted: 2

Decision support only. Final interpretation remains with the qualified clinical team.

Affected records in full

Synthetic demonstration data

Record	Age band	Test date	As reported	Current	Department	Clinical owner	Last contact	Review state
VP-10543	35-44	11 Oct 2022	VUS	Likely pathogenic	Lipid Clinic	Dr. H. Nassar	3y ago	Not reviewed
VP-10580	12-17	23 Jan 2023	VUS	Likely pathogenic	Lipid Clinic	Dr. H. Nassar	4y ago	Not reviewed

Source

Classification

Review level

Last updated

Strength

ClinVar10 submissions on record.

Likely pathogenic

Reviewed by expert panel

23 Feb 2024

Strong

VCV000183113

Population frequencyHighest reported allele frequency carried on the source record.

1.00e-5

The Genome Aggregation Database (gnomAD)

23 Feb 2024

Reference observation

LiteraturePublications linked to this variant record.

8 indexed publications

PubMed index

Latest 2022

Supporting context

Regional Evidence IndexModelled regional aggregation maintained inside this workspace

Likely pathogenic

0 regional observations

27 Jan 2026

Cohort 3,042

This institutionThe interpretation issued to the patient at the time of testing.

Uncertain significance

Internal report

11 Oct 2022

On record

Record

Age band

Test date

As reported

Current

Department

Clinical owner

Last contact

Review state

VP-10543

35-44

11 Oct 2022

VUS

Likely pathogenic

Lipid Clinic

Dr. H. Nassar

3y ago

Not reviewed

VP-10580

12-17

23 Jan 2023

VUS

Likely pathogenic

Lipid Clinic

Dr. H. Nassar

4y ago

Not reviewed