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.1957G>T (p.Val653Phe)

CA10585695

252129 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: a144e629-27a6-411b-9541-dd30a4ea5262

Approved on: 2024-02-23

Published on: 2025-09-15

HGVS expressions

NM_000527.5(LDLR):c.1957G>T (p.Val653Phe)

NM_000527.5:c.1957G>T

NC_000019.10:g.11120203G>T

CM000681.2:g.11120203G>T

NC_000019.9:g.11230879G>T

CM000681.1:g.11230879G>T

NC_000019.8:g.11091879G>T

NG_009060.1:g.35823G>T

ENST00000252444.10:c.2215G>T

ENST00000559340.2:c.*26G>T

ENST00000560467.2:c.1837G>T

ENST00000558518.6:c.1957G>T

ENST00000252444.9:c.2211G>T

ENST00000455727.6:c.1453G>T

ENST00000535915.5:c.1834G>T

ENST00000545707.5:c.1576G>T

ENST00000557933.5:c.1957G>T

ENST00000558013.5:c.1957G>T

ENST00000558518.5:c.1957G>T

ENST00000559340.1:c.538G>T

NM_000527.4:c.1957G>T

NM_001195798.1:c.1957G>T

NM_001195799.1:c.1834G>T

NM_001195800.1:c.1453G>T

NM_001195803.1:c.1576G>T

NM_001195798.2:c.1957G>T

NM_001195799.2:c.1834G>T

NM_001195800.2:c.1453G>T

NM_001195803.2:c.1576G>T

Uncertain Significance

PP4 PM2 PS4_Supporting

BP2 BP4 PP1 PP3 PM5 PS3

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

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Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5 (LDLR):c.1957G>T (p.Val653Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, 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). PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 unrelated index cases fulfilling criteria for FH (3 cases with DLCN score >=6 from reported in VCI by Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case meeting Simon Broome criteria reported in VCI by Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP. Sorbonne Université, Hospital de la Pitié-Salpêtrière, France; 1 case meeting Simon Broome criteria in PMID 14974088 (Dedoussis et al., 2004), from Harokopio University of Athens, Greece).

PP4

Variant meets PM2, and is identified in >1 index cases who fulfil FH criteria after alternative causes of high cholesterol were excluded.

PM2

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

PS4_Supporting

Variant meets PM2, and is identified in 5 unrelated index cases fulfil FH criteria. Three cases fulfil DLCN ≥6 reported in VCI by Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. Two cases fulfil Simon Broome criteria, one case reported in VCI by Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP. Sorbonne Université, Hospital de la Pitié-Salpêtrière); one case reported in PMID 14974088 by Dedoussis et al, 2004, from Harokopio University of Athens, Greece.

BP2

Variant identified in a patient with heterozygous FH phenotype who also carries NM_000527.5 (LDLR):c.1171G>A (p.Ala391Thr) and confirmed in trans. However LDLR: p.A391T is classified as Benign by these guidelines, therefore BP2 is not met. This index case is reported in PMID 14974088 by Dedoussis et al, 2004, from Harokopio University of Athens, Greece.

BP4

REVEL=0.69, it is not above 0.75, splicing evaluation required. MES: A) Variant not on limits. B) Variant not on limit creating de novo acceptor; variant on limit and created GT, Var de novo score/Wt score = -18.11/10.28 = -1.76, which is less than 0.8. C) There is not a GT nearby. Variant is not predicted to alter splicing, and result is confirmed by SpliceAI. REVEL score for the variant is between 0.5 and 0.75, therefore PP3/BP4 is not met.

PP1

Variant segregates with FH phenotype in 1 (less than 2) informative meiosis, one affected relative tested positive for the variant from 1 family, reported in PMID 14974088 by Dedoussis et al, 2004, from Harokopio University of Athens, Greece.

PP3

PM5

Three other missense variants in the same codon: NM_000527.5 (LDLR):c.1958T>G (p.Val653Gly) (ClinVar ID 252130), classified as VUS; NM_000527.5 (LDLR):c.1957G>A (p.Val653Ile) (ClinVar ID 628891), classified as VUS; NM_000527.5 (LDLR):c.1958_1959delinsCC (p.Val653Ala) (ClinVar ID 1008168), classified as VUS by these guidelines, therefore PM5 is not met.

PS3

Functional data not available.

Curation History

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