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]

Variant: NM_000527.5(LDLR):c.283T>G (p.Cys95Gly)

CA10584825

251112 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 0cd36ed2-b053-4bf7-9626-482b541fde93

Approved on: 2024-02-23

Published on: 2025-08-29

HGVS expressions

NM_000527.5(LDLR):c.283T>G (p.Cys95Gly)

NM_000527.5:c.283T>G

NC_000019.10:g.11102756T>G

CM000681.2:g.11102756T>G

NC_000019.9:g.11213432T>G

CM000681.1:g.11213432T>G

NC_000019.8:g.11074432T>G

NG_009060.1:g.18376T>G

ENST00000252444.10:c.541T>G

ENST00000559340.2:c.283T>G

ENST00000560467.2:c.283T>G

ENST00000558518.6:c.283T>G

ENST00000252444.9:c.537T>G

ENST00000455727.6:c.283T>G

ENST00000535915.5:c.190+2411T>G

ENST00000545707.5:c.283T>G

ENST00000557933.5:c.283T>G

ENST00000557958.1:n.369T>G

ENST00000558013.5:c.283T>G

ENST00000558518.5:c.283T>G

NM_000527.4:c.283T>G

NM_001195798.1:c.283T>G

NM_001195799.1:c.190+2411T>G

NM_001195800.1:c.283T>G

NM_001195803.1:c.283T>G

NM_001195798.2:c.283T>G

NM_001195799.2:c.190+2411T>G

NM_001195800.2:c.283T>G

NM_001195803.2:c.283T>G

Likely Pathogenic

PS4_Supporting PP4 PP3 PM2 PM1

PVS1 BS2 BS4 BS3 BS1 BP5 BP7 BP3 BP4 BP1 PS3 PP1 PP2 BA1 PM5 PM3 PM4

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.283T>G (p.Cys95Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.949. PM1: Variant meets PM2 and alters one highly conserved Cys residue (Cys95). PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill clinical diagnostic criteria for FH (1 case from Spain with MedPed criteria in PMID 16627557 (Blesa et al., 2006), and 2 cases from Japan meeting Japan Atherosclerosis Society criteria in PMID 18718593 (Miyake et al., 2009)).

PS4_Supporting

Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill clinical diagnostic criteria for FH. One case (Spain) with MedPed criteria in PMID: 16627557, and two cases (Japan) with national Japanese (Japan Atherosclerosis Society) criteria in PMID: 18718593.

PP4

- PP4: Variant meets PM2 and is identified in at least 1 index case fulfilling clinical diagnostic criteria for FH, after alternative causes of high cholesterol were excluded.

PP3

PP3: REVEL = 0.949. It is above 0.75, so PP3 is met.

PM2

PM2: This variant is absent from gnomAD (gnomAD v2.1.1).

PM1

Variant meets PM2 and alters one higly conserved Cys residue (Cys95).

PVS1

This variant is misense, therefore PVS1 is not met.

BS2

not met, (no information of several index cases or segregation data/cases in different families)

BS4

not met, (no information of several index cases or segregation data/cases in different families)

BS3

not met. Functional studies (PMID: 18718593) Level 2 assay using compound heterozygous (with p.(Leu568Val)) patients' fibroblasts, 125I-LDL assays - results - 20% LDL-LDLR binding. Due to compHtz, PS3 was not considered.

BS1

This variant is absent from gnomAD (gnomAD v2.1.1), therefore BS1 is not met.

BP5

N/A according to FH VCEP Guidelines

BP7

This variant is misense, therefore BP7 is not met.

BP3

N/A according to FH VCEP Guidelines

BP4

BP4: REVEL = 0.949, not bellow 0.50. Therefore, BP4 is not met.

BP1

N/A according to FH VCEP Guidelines

PS3

PP1

not met, (no information of several index cases or segregation data/cases in different families)

PP2

N/A according to FH VCEP Guidelines

BA1

This variant is absent from gnomAD (gnomAD v2.1.1), therefore BA1 is not met.

PM5

* PM5 / PS1 not met: NM_000527.5(LDLR):c.284G>A (p.Cys95Tyr) (ClinVar ID: 251113) considered as Likely Pathogenic by these guidelines

PM3

* PM3: (PMID:18718593) Variant meets PM2 and was identified in one index case with homozygous FH phenotype (LDL-c 403 mg/dL) and LDLR variant c.1702C>G/p.(Leu568Val). Not confirmed if the variant was detected in trans // (PMID:19007590) Variant meets PM2 and was identified in one index case with homozygous FH phenotype (LDL-c 398 mg/dL) and LDLR variant 1587-1G>C. Not confirmed if the variant was detected in trans.

PM4

This variant is misense, therefore PM4 is not met.

Curation History

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