VP-R-2026-002

LDLR c.1706-10G>A

Familial hypercholesterolaemia

Needs reviewMedium

Classification change

Then2021

Uncertain significance

As reported

Science changed

Now2022

Likely benign

Reviewed by expert panel

Regional conflict

Variant

Gene: LDLR
HGVS (coding): c.1706-10G>A
Protein: Not applicable
ClinVar: VCV000226368
dbSNP: rs17248882
Panel: Lipid disorders panel
Molecular consequence: intron variant

Patient impact

Records carrying this variant.

VP-1012245-54 · Lipid Clinic9 Aug 2021Dr. H. Nassar

How the interpretation changed

LDLR c.1706-10G>A — the DNA is unchanged. The evidence around it is not.

2021Genetic test performedFirst record on file carrying LDLR c.1706-10G>A.
2021Reported as uncertain significanceIntronic change near the splice acceptor. Splicing impact undetermined at the time of reporting.
2022Further literature published2 indexed publications appeared after the original report.
2022Submissions accumulated32 independent submissions now contribute to the classification.
2022Classification now likely benignLast evaluated 16 Mar 2022 · Reviewed by expert panel.
TodayVariantPulse identified the affected recordsOne historical record carries this variant and was flagged for clinical review.

Evidence summary

Decision support

Global and regional evidence disagree on LDLR c.1706-10G>A. The global consensus is likely benign, drawn from 32 submissions. The regional index asserts likely pathogenic on 14 observations across a cohort of 6,850. One source places this variant in the clinically actionable band and the other does not, which is the form of disagreement most likely to change a care decision. One record on file carries this variant and has not yet been reassessed.

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

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
ClinVar32 submissions on record.	Likely benign	Reviewed by expert panel	16 Mar 2022	Strong3 of 4 review criteria met	VCV000226368
Population frequencyHighest reported allele frequency carried on the source record.	0.00253	Exome Aggregation Consortium (ExAC)	16 Mar 2022	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	14 regional observations	11 Feb 2026	Cohort 6,850
This institutionThe interpretation issued to the patient at the time of testing.	Uncertain significance	Internal report	9 Aug 2021	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
The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. — Genet Med 2022 · PMID 34906454
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
Development of a new expanded next-generation sequencing panel for genetic diseases involved in dyslipidemia. — Clin Genet 2020 · PMID 33111339
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. — Genet Med 2017 · PMID 28492532
Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals. — Eur J Hum Genet 2017 · PMID 28145427
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 diagnosis of familial hypercholesterolaemia using a rapid biochip array assay for 40 common LDLR, APOB and PCSK9 mutations. — Atherosclerosis 2016 · PMID 27680772

Global and regional evidence

Regional conflict

Global

Likely benign

Submissions: 32
Review status: Reviewed by expert panel
Last evaluated: 16 Mar 2022
Reference frequency: 2.53e-3

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

Regional

Likely pathogenic

Observations: 14
Cohort size: 6,850
Last updated: 11 Feb 2026
Regional frequency: 2.10e-3

Modelled regional aggregation maintained inside this workspace.

VariantPulse analysis

One source places this variant in the clinically actionable band and the other does not. Enriched in regional familial hypercholesterolaemia cohorts relative to the global reference set, with a splice-impact signal reported in affected families. The mutation spectrum of familial hypercholesterolaemia across Arab countries is documented as distinct from European cohorts, so a benign reading derived largely from European data does not settle the question here.

VariantPulse recommends manual review due to conflicting interpretation across evidence sources. It does not rank one source above the other.

Spectrum of mutations of familial hypercholesterolemia in the 22 Arab countries. — Atherosclerosis 2018 · PMID 30415195
The Spectrum of Familial Hypercholesterolemia (FH) in Saudi Arabia: Prime Time for Patient FH Registry. — Open Cardiovasc Med J 2017 · PMID 28868092

How VariantPulse reached this resultEight steps, each one inspectable

1Historical record retrievedLDLR c.1706-10G>A reported as Uncertain significance on 2021-08-09.
2Variant normalisedResolved to ClinVar VCV000226368 (rs17248882) and keyed as LDLR:c.1706-10G>A.
3Current evidence retrievedRead live from ClinVar: Likely benign, 32 submissions, reviewed by expert panel.
4Classification difference detectedRecorded interpretation normalised to Uncertain significance. Current interpretation normalised to Likely benign. Evidence moved toward a benign interpretation.
5Regional sources comparedRegional index asserts Likely pathogenic across 14 observations. One source places this variant in the clinically actionable band and the other does not.
6Impacted records identified12,482 findings checked; 1 carries 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.

+30Regional evidence conflictsRegional and global sources reach different conclusions.
+51 record on fileHistorical results carrying this variant that a reviewer would reassess.
+10High review confidenceThe current classification carries expert-panel or guideline review.

Ordering score45

Case notes

No notes on this case yet.

Recommendation

Manual review recommended: global and regional sources disagree, and VariantPulse does not rank one above the other. A clinician should weigh both against the patient context.

Approving records a review decision inside VariantPulse. It does not write to any patient record and does not issue a diagnosis.

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Case detail

Case: VP-R-2026-002
Raised: just now
Assigned: Unassigned
Evidence source: ClinVar (live)
Records impacted: 1

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

Affected records in full

Record	Age band	Test date	As reported	Current	Department	Clinical owner	Last contact	Review state
VP-10122	45-54	9 Aug 2021	VUS	Likely benign	Lipid Clinic	Dr. H. Nassar	2y ago	Not reviewed

Source

Classification

Review level

Last updated

Strength

ClinVar32 submissions on record.

Likely benign

Reviewed by expert panel

16 Mar 2022

Strong

VCV000226368

Population frequencyHighest reported allele frequency carried on the source record.

0.00253

Exome Aggregation Consortium (ExAC)

16 Mar 2022

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

14 regional observations

11 Feb 2026

Cohort 6,850

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

Uncertain significance

Internal report

9 Aug 2021

On record

Record

Age band

Test date

As reported

Current

Department

Clinical owner

Last contact

Review state

VP-10122

45-54

9 Aug 2021

VUS

Likely benign

Lipid Clinic

Dr. H. Nassar

2y ago

Not reviewed