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.298G>A (p.Asp100Asn)

CA10584832

251121 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 2a5e70a7-3328-461c-97ec-ad2a36bcd68d

HGVS expressions

NM_000527.5:c.298G>A

NM_000527.5(LDLR):c.298G>A (p.Asp100Asn)

NC_000019.10:g.11102771G>A

CM000681.2:g.11102771G>A

NC_000019.9:g.11213447G>A

CM000681.1:g.11213447G>A

NC_000019.8:g.11074447G>A

NG_009060.1:g.18391G>A

ENST00000558518.6:c.298G>A

ENST00000252444.9:n.552G>A

ENST00000455727.6:c.298G>A

ENST00000535915.5:c.190+2426G>A

ENST00000545707.5:c.298G>A

ENST00000557933.5:c.298G>A

ENST00000557958.1:n.384G>A

ENST00000558013.5:c.298G>A

ENST00000558518.5:c.298G>A

NM_000527.4:c.298G>A

NM_001195798.1:c.298G>A

NM_001195799.1:c.190+2426G>A

NM_001195800.1:c.298G>A

NM_001195803.1:c.298G>A

NM_001195798.2:c.298G>A

NM_001195799.2:c.190+2426G>A

NM_001195800.2:c.298G>A

NM_001195803.2:c.298G>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PP1 PP4 PP3 PS4_Supporting PM2 PM3

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.298G>A (p.Asp100Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PP1, PP3, PP4, PS4_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: This variant is absent from gnomAD (gnomAD v2.1.1) - PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL-C=10.25 mmol/L ) as homozygous status, from PMID: 25936346. - PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family from PMID: 25936346 - PP3: REVEL = 0.93 - PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible FH from Ambry Genetics, after alternative causes for high cholesterol were excluded. - PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with Simon-Broome criteria of possible FH from Ambry Genetics, 1 cases with Simon-Broome criteria of possible FH from PMID: 25936346)

PP1

Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family from PMID: 25936346

PP4

Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible FH from Ambry Genetics, after alternative causes for high cholesterol were excluded.

PP3

REVEL = 0.93

PS4_Supporting

Variant meets PM2 and is identified in 2 index cases (1 case with Simon-Broome criteria of possible FH from Ambry Genetics, 1 cases with Simon-Broome criteria of possible FH from PMID: 25936346)

PM2

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

PM3

Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL-C=10.25 mmol/L ) as homozygous status, from PMID: 25936346.

Approved on: 2023-04-28

Published on: 2023-05-01

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