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.1090T>C (p.Cys364Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585298

251657 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 83db5c0d-e02c-4534-a6b3-3d2b3f49ec5b

Approved on: 2025-03-24

Published on: 2025-03-24

HGVS expressions

NM_000527.5:c.1090T>C

NM_000527.5(LDLR):c.1090T>C (p.Cys364Arg)

NC_000019.10:g.11111543T>C

CM000681.2:g.11111543T>C

NC_000019.9:g.11222219T>C

CM000681.1:g.11222219T>C

NC_000019.8:g.11083219T>C

NG_009060.1:g.27163T>C

ENST00000252444.10:c.1348T>C

ENST00000559340.2:c.1090T>C

ENST00000560467.2:c.970T>C

ENST00000558518.6:c.1090T>C

ENST00000252444.9:c.1344T>C

ENST00000455727.6:c.586T>C

ENST00000535915.5:c.967T>C

ENST00000545707.5:c.709T>C

ENST00000557933.5:c.1090T>C

ENST00000558013.5:c.1090T>C

ENST00000558518.5:c.1090T>C

ENST00000560173.1:n.89T>C

ENST00000560467.1:c.570T>C

NM_000527.4:c.1090T>C

NM_001195798.1:c.1090T>C

NM_001195799.1:c.967T>C

NM_001195800.1:c.586T>C

NM_001195803.1:c.709T>C

NM_001195798.2:c.1090T>C

NM_001195799.2:c.967T>C

NM_001195800.2:c.586T>C

NM_001195803.2:c.709T>C

Likely Pathogenic

PS4_Supporting PP4 PP3 PM2 PM3 PM1 PP1_Moderate

PS3 PS1 BA1 PM5 BS4 BS3 BS1 BP2 BP4

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.1090T>C (p.Cys364Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PM3, PP1_Moderate, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: PM1: Variant meets PM2 and alters Cys364, one of the highly conserved cysteine residues listed. PM2: PopMax MAF=0.00001666 (0.001666%) in Admixed American exomes + genomes (gnomAD v4.1.0). PP3: REVEL=0.984. PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases (1 case with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism, Italy; 1 case with modified Simon-Broome criteria from PMID 23064986 (Ahmad et al., 2012), USA). PP1_Moderate: Variant segregates with FH phenotype in 5 informative meiosis from 2 families from different labs (Laboratory of Genetics and Molecular Cardiology, Brazil and Research Lab of Molecular Genetics of Lipid Metabolism, Italy): 3 affected family members have the variant and 2 unaffected family members do not have the variant. PM3: Variant meets PM2 and is identified in at least 1 clinically diagnosed HoFH, homozygous for the variant (PMID 37119068; PMID 27940769).

PS4_Supporting

Variant meets PM2 and is identified in 2 unrelated index cases (1 case with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism, Italy; 1 case with modified Simon-Broome criteria from PMID 23064986 (Ahmad et al., 2012), USA).

PP4

Variant meets PM2 and is identified in 2 index cases (see PS4 for details), after alternative causes of high cholesterol were excluded.

PP3

REVEL = 0.984, it is above 0.75

PM2

PopMax MAF = 0.00001666 (0.001666%) in Admixed American exomes+genomes (gnomAD v4.1.0).

PM3

Variant meets PM2 and is identified in at least 1 clinically diagnosed HoFH homozygous for the variant: 1 from the CASCADE FH Registry (PMID: 37119068) and in a 7y old boy with cLDL=946 mg/dL, xanthomas+aortic valve stenosis (PMID: 27940769), both in USA.

PM1

Variant meets PM2, is missense in exon 4, and alters Cys364, one of the cysteine residues listed.

PP1_Moderate

Variant segregates with FH phenotype in 5 informative meiosis in 2 families from different labs (Laboratory of Genetics and Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine): 3 affected family members have the variant and 2 unaffected family members do not have the variant.

PS3

Compound heterozygous, should we use this evidence?

PS1

Variant meets PM1, and there is one more missense variant that is classified as Likely Pathogenic.

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

Variant meets PM1, and there is one more missense variant that is classified as Likely Pathogenic.

BS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP2

Cis/trans status is unknown

BP4

REVEL = 0.984, it is above 0.75

Curation History

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