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.895G>A (p.Ala299Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585179

251507 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

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

Approved on: 2022-02-10

Published on: 2022-04-25

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

PP4 PM2 PS3_Supporting PS4_Supporting

PP3 PM5

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.

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.

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).

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.

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.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.