Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000527.5(LDLR):c.1061-8T>C

CA023412

36451 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: ae8305b5-add5-4562-92bb-5b2df2ce6396

Approved on: 2022-03-25

Published on: 2022-04-25

HGVS expressions

NM_000527.5:c.1061-8T>C

NM_000527.5(LDLR):c.1061-8T>C

NC_000019.10:g.11111506T>C

CM000681.2:g.11111506T>C

NC_000019.9:g.11222182T>C

CM000681.1:g.11222182T>C

NC_000019.8:g.11083182T>C

NG_009060.1:g.27126T>C

ENST00000558518.6:c.1061-8T>C

ENST00000252444.9:n.1315-8T>C

ENST00000455727.6:c.557-8T>C

ENST00000535915.5:c.938-8T>C

ENST00000545707.5:c.680-8T>C

ENST00000557933.5:c.1061-8T>C

ENST00000558013.5:c.1061-8T>C

ENST00000558518.5:c.1061-8T>C

ENST00000560173.1:n.60-8T>C

ENST00000560467.1:n.541-8T>C

NM_000527.4:c.1061-8T>C

NM_001195798.1:c.1061-8T>C

NM_001195799.1:c.938-8T>C

NM_001195800.1:c.557-8T>C

NM_001195803.1:c.680-8T>C

NM_001195798.2:c.1061-8T>C

NM_001195799.2:c.938-8T>C

NM_001195800.2:c.557-8T>C

NM_001195803.2:c.680-8T>C

Benign

BA1 BS3_Supporting

BP2

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5 (LDLR):c.1061-8T>C variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BA1: PopMax FAF = 0.008564 in African/African American population in gnomAD (gnomAD v2.2.1). BS3_Supporting: Heterozygous patient cells were used for RNA assays (Level 3 experiment) shown normal LDLR transcripts reported from 2 research labs: Bourbon et al, Unidade de Investigacao Cardiovascular, Instituto Nacional de Saude Dr. Ricardo Jorge, Lisboa, Portugal, (PMID 19411563); Holla et al, Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway, (PMID 19208450). Functional studies is consistent with no damaging effect.

BA1

PopMax FAF = 0.008564 in African/African American population in gnomAD (gnomAD v2.2.1).

BS3_Supporting

Heterozygous patient cells were used for RNA assays (Level 3 experiment) shown normal LDLR transcripts reported from 2 research labs: Bourbon et al, Unidade de Investigacao Cardiovascular, Instituto Nacional de Saude Dr. Ricardo Jorge, Lisboa, Portugal, (PMID 19411563); Holla et al, Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway, (PMID 19208450). Functional studies is consistent with no damaging effect.

BP2

At least 2 index cases also carry LDLR:c.2177C>T,p.T726I, identified from 2 different labs. One case was confirmed that 2 variants are in trans (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge); 1 case was identified with unknown phase of 2 variants (Robarts Research Institute). Variant LDLR:c.2177C>T,p.T726I is classified as Benign by these guidelines, therefore BP2 is not met.

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