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>A (p.Val653Ile)

CA404093185

628891 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: ea1ab271-3d8b-4108-8df4-94bcbdeb55c3

Approved on: 2024-02-23

Published on: 2025-09-15

HGVS expressions

NM_000527.5(LDLR):c.1957G>A (p.Val653Ile)

NM_000527.5:c.1957G>A

NC_000019.10:g.11120203G>A

CM000681.2:g.11120203G>A

NC_000019.9:g.11230879G>A

CM000681.1:g.11230879G>A

NC_000019.8:g.11091879G>A

NG_009060.1:g.35823G>A

ENST00000252444.10:c.2215G>A

ENST00000559340.2:c.*26G>A

ENST00000560467.2:c.1837G>A

ENST00000558518.6:c.1957G>A

ENST00000252444.9:c.2211G>A

ENST00000455727.6:c.1453G>A

ENST00000535915.5:c.1834G>A

ENST00000545707.5:c.1576G>A

ENST00000557933.5:c.1957G>A

ENST00000558013.5:c.1957G>A

ENST00000558518.5:c.1957G>A

ENST00000559340.1:c.538G>A

NM_000527.4:c.1957G>A

NM_001195798.1:c.1957G>A

NM_001195799.1:c.1834G>A

NM_001195800.1:c.1453G>A

NM_001195803.1:c.1576G>A

NM_001195798.2:c.1957G>A

NM_001195799.2:c.1834G>A

NM_001195800.2:c.1453G>A

NM_001195803.2:c.1576G>A

Uncertain Significance

BP4 PP4 PM2

PS3 PM5

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.1957G>A (p.Val653Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 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 in all specified genetic ancestry groups (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 index case who meets Simon Broome criteria for FH after alternative causes of high cholesterol were excluded, 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. BP4: REVEL=0.372, it is below 0.5, splicing evaluation required. MES: A) variant not on limits. B) Variant not on limit creating de novo acceptor; variant is on limit however does not create GT. C) there is not a GT nearby. Variant is not predicted to alter splicing, and result is confirmed by SpliceAI, therefore BP4 is met.

BP4

REVEL=0.372, it is below 0.5, splicing evaluation required. MES: A) variant not on limits. B) Variant not on limit creating de novo acceptor; variant is on limit however does not create GT. C) there is not a GT nearby. Variant is not predicted to alter splicing, and result is confirmed by SpliceAI, therefore BP4 is met.

PP4

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

PM2

This variant is absent in all specified genetic ancestry groups (gnomAD v2.1.1).

PS3

Functional data not available.

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>T (p.Val653Phe) (ClinVar ID 252129), 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.

Curation History

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