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.352G>T (p.Asp118Tyr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023697

183085 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e8a7cc28-f4d2-40e2-808b-9f8b9c94219c

Approved on: 2024-02-23

Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.352G>T

NM_000527.5(LDLR):c.352G>T (p.Asp118Tyr)

NC_000019.10:g.11105258G>T

CM000681.2:g.11105258G>T

NC_000019.9:g.11215934G>T

CM000681.1:g.11215934G>T

NC_000019.8:g.11076934G>T

NG_009060.1:g.20878G>T

ENST00000252444.10:c.610G>T

ENST00000559340.2:c.352G>T

ENST00000560467.2:c.352G>T

ENST00000558518.6:c.352G>T

ENST00000252444.9:c.606G>T

ENST00000455727.6:c.314-2134G>T

ENST00000535915.5:c.229G>T

ENST00000545707.5:c.314-1307G>T

ENST00000557933.5:c.352G>T

ENST00000558013.5:c.352G>T

ENST00000558518.5:c.352G>T

NM_000527.4:c.352G>T

NM_001195798.1:c.352G>T

NM_001195799.1:c.229G>T

NM_001195800.1:c.314-2134G>T

NM_001195803.1:c.314-1307G>T

NM_001195798.2:c.352G>T

NM_001195799.2:c.229G>T

NM_001195800.2:c.314-2134G>T

NM_001195803.2:c.314-1307G>T

Likely Pathogenic

PP4 PP1 PM2 PM1 PS4_Moderate

BP4 BP2 PS3 PP3 PM3 PM5 BS4 BS3

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.352G>T (p.Asp118Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Moderate, PM1, PM2, PP1 and PP4 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: PopMax MAF = 0.000004496 (0.0004%) in European (non-Finnish) exomes (gnomAD v4.0.0). PM1: Variant meets PM2 and is missense in exon 4. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (1 case with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; 4 cases with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy; 1 case with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia). PP1: Variant segregates with phenotype in 2 informative meiosis in 2 families from different labs (1 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France, and 1 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy): 2 affected family members have the variant.

PP4

PP4 - Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH, after alternative causes of high cholesterol were excluded (see PS4 for details).

PP1

PP1 - Variant segregates with phenotype in 2 informative meiosis in 2 families from different labs: 1 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) and 1 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine)

PM2

PM2 - PopMax MAF = 0.000004496 (0.0004%) in European (non-Finnish) exomes (gnomAD v4.0.0)

PM1

PM1 - Variant meets PM2 and is missense (exon 4).

PS4_Moderate

PS4_Moderate: Variant meets PM2 and was found in 6 unrelated index cases: 1 with Simone-Broome from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), 4 with DLCN score >6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine and 1 with DLCN criteria >6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA).

BP4

BP4_Not Met: REVEL is not <0.50.

BP2

BP2_Not Met: 4 individuals with HeFH phenotype from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine with c.1187-7C>A (in cis).

PS3

PS3_Not Met: in PMID: 9974426 and PMID: 25647241 there aren't functional evidence for this variant.

PP3

PP3_Not Met: REVEL=0.66, splicing evaluation needed. A) Variant not on limits B) does not create AG C) there is an AG nearby MES score: variant cryptic site=-8.43, wt cryptic site=-8.56, canonical donor site=8.16 Ratio variant cryptic site/wt cryptic site= -8.43/-8.56-=0.98 --- not > 1.1 Ratio variant cryptic site/canonical donor site= -8.43/8.16= -1.03 --- not > 0.9 PP3 is not met.

PM3

PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype in Bertolini et al., 1999 (PMID 9974426) with LDL = 12.58mmol/L and compound heterozygous for c.1567G>T, p.Val523Met, classified by the FH VCEP as Likely pathogenic. However, LDL is not >13 mmol/L and the variants have not been confirmed to be in trans.

PM5

PM5 - Missense variants at the same codon predicting a different amino acid change (Asp118Asn, Asp118Ala), but variants are only classified as of uncertain significance by these guidelines.

BS4

BS4 - Variant does not segregate with FH phenotype in 2 informative meiosis in 2 families from 2 different labs: Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies - APHP Sorbonne Université, Hôpital de la Pitié-Salpêtrière and Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine). However, no unaffected relatives were positive for the variant, so BS4 cannot be applied.

BS3

BS3_Not Met: in PMID: 9974426 and PMID: 25647241 there aren't functional evidence for this variant.

Curation History

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