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.2023G>A (p.Gly675Ser)

CA038175

252173 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 65363e52-5d51-4ffc-b1e6-b36bf508f027

Approved on: 2024-07-02

Published on: 2024-09-19

HGVS expressions

NM_000527.5:c.2023G>A

NM_000527.5(LDLR):c.2023G>A (p.Gly675Ser)

NC_000019.10:g.11120405G>A

CM000681.2:g.11120405G>A

NC_000019.9:g.11231081G>A

CM000681.1:g.11231081G>A

NC_000019.8:g.11092081G>A

NG_009060.1:g.36025G>A

ENST00000252444.10:c.2281G>A

ENST00000559340.2:c.*92G>A

ENST00000560467.2:c.1903G>A

ENST00000558518.6:c.2023G>A

ENST00000252444.9:c.2277G>A

ENST00000455727.6:c.1519G>A

ENST00000535915.5:c.1900G>A

ENST00000545707.5:c.1606+172G>A

ENST00000557933.5:c.2023G>A

ENST00000558013.5:c.2023G>A

ENST00000558518.5:c.2023G>A

ENST00000559340.1:c.604G>A

NM_000527.4:c.2023G>A

NM_001195798.1:c.2023G>A

NM_001195799.1:c.1900G>A

NM_001195800.1:c.1519G>A

NM_001195803.1:c.1606+172G>A

NM_001195798.2:c.2023G>A

NM_001195799.2:c.1900G>A

NM_001195800.2:c.1519G>A

NM_001195803.2:c.1606+172G>A

Likely Pathogenic

PS4_Supporting PP1_Strong PP4 PP3 PM2

PM3

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.2023G>A (p.Gly675Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.000008856 (0.0008856%) in European (non-Finnish) exomes (gnomAD v2.1.1). PP3: REVEL = 0.853. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 unrelated index cases who fulfill criteria for FH (2 cases with possible FH by Simon Broome criteria and 2 cases with DLCN score >=6 from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793; 1 case from PMID 27824480). PP1_Strong: Variant segregates with FH phenotype in at least 8 informative meioses from 4 families (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic): 5 affected family members have the variant and 3 unaffected family members do not have the variant.

PS4_Supporting

Variant meets PM2 and is identified in at least 5 unrelated index cases who fulfill SB definite FH (PMIDs: 22698793 and 27824480, Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation). PMID 27824480: 1 case meeting SB definite FH criteria Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation: 2 cases with possible FH by Simon Broome criteria and 2 cases with DLCN score >=6

PP1_Strong

Variant segregates with FH phenotype in at least 8 informative meioses from four families (Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) Data is from 4 families (F1,2,3 and 5): F1: 1 relative with the variant and LDL>75th percentile; F2: 1 relative with the variant and LDL>75th percentile, plus 2 relatives without the variant and with LDL<50th percentile; F3: 1 relative with the variant and LDL>75th percentile; F5: 2 relatives with the variant and LDL>75th percentile, plus 1 relative without the variant and with LDL<50th percentile

PP4

Variant meets PM2 and is identified in at least 1 index case who fulfills SB definite FH (PMID: 11754108) after alternative causes of high cholesterol were excluded.

PP3

REVEL = 0.853

PM2

PopMax MAF = 0.000008856 (0.0008856%) in European (non-Finnish) exomes (gnomAD v2.1.1).

PM3

Did not find any patients with variant who had LDL-C > 13 mmol/L

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.