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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.895G>A (p.Ala299Thr)

CA10585179

251507 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e8a3d2ee-ecdb-4871-9de7-6eb61f054674

HGVS expressions

NM_000527.5:c.895G>A

NM_000527.5(LDLR):c.895G>A (p.Ala299Thr)

NC_000019.10:g.11107469G>A

CM000681.2:g.11107469G>A

NC_000019.9:g.11218145G>A

CM000681.1:g.11218145G>A

NC_000019.8:g.11079145G>A

NG_009060.1:g.23089G>A

ENST00000558518.6:c.895G>A

ENST00000252444.9:n.1149G>A

ENST00000455727.6:c.391G>A

ENST00000535915.5:c.772G>A

ENST00000545707.5:c.514G>A

ENST00000557933.5:c.895G>A

ENST00000558013.5:c.895G>A

ENST00000558518.5:c.895G>A

ENST00000558528.1:n.410G>A

ENST00000560467.1:n.495G>A

NM_000527.4:c.895G>A

NM_001195798.1:c.895G>A

NM_001195799.1:c.772G>A

NM_001195800.1:c.391G>A

NM_001195803.1:c.514G>A

NM_001195798.2:c.895G>A

NM_001195799.2:c.772G>A

NM_001195800.2:c.391G>A

NM_001195803.2:c.514G>A

Uncertain Significance

PM2 PS3_Supporting PS4_Supporting PP4

PM5 PP3

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.895G>A (p.Ala299Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, PS3_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: PM2 Met: PopMAX MAF = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in > 1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting Met: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH (1 case from Unidad de Biof´ısica , Centro Mixto CSIC-UPV/EHU and Departamento de Bioqu´ımica, Universidad del Pa´ıs Vasco, Bilbao, Spain, PMID 21990180; 1 case from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain, PMID 19318025). PS3_Supporting Met: Heterozygous patient lymphocytes FACS assays (level 3 functional assay) showed normal cell surface localization, but 50% LDL-LDLR uptake and binding (Etxebarria et al, Unidad de Biof´ısica, Centro Mixto CSIC-UPV/EHU and Departamento de Bioqu´ımica, Universidad del Pa´ıs Vasco, Bilbao, Spain, PMID 21990180). PP3 not met: REVEL score = 0.543, which is below the threshold of 0.75. This variant does not creating de novo acceptor or donor site and is not predicted to alter splicing. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.895G>T (p.Ala299Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.

PM2

PopMAX MAF = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1).

PS3_Supporting

Heterozygous patient lymphocytes FACS assays (level 3 functional assay) showed normal cell surface localization, but 50% LDL-LDLR uptake and binding (Etxebarria et al, Unidad de Biof´ısica, Centro Mixto CSIC-UPV/EHU and Departamento de Bioqu´ımica, Universidad del Pa´ıs Vasco, Bilbao, Spain, PMID 21990180).

PS4_Supporting

Variant meets PM2 and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH (1 case from Unidad de Biof´ısica , Centro Mixto CSIC-UPV/EHU and Departamento de Bioqu´ımica, Universidad del Pa´ıs Vasco, Bilbao, Spain, PMID 21990180; 1 case from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain, PMID 19318025).

PP4

This variant meets PM2 and is identified in > 1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded.

PM5

There is one other variant in the same codon: LDLR: NM_000527:c.895G>T (p.Ala299Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.

PP3

REVEL score = 0.543, which is below the threshold of 0.75. This variant does not creating de novo acceptor or donor site and is not predicted to alter splicing.

Approved on: 2022-02-10

Published on: 2022-04-25

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