NM_000527.5(LDLR):c.953G>A (p.Cys318Tyr) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 29, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003165667.2

Allele description [Variation Report for NM_000527.5(LDLR):c.953G>A (p.Cys318Tyr)]

NM_000527.5(LDLR):c.953G>A (p.Cys318Tyr)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.953G>A (p.Cys318Tyr)

Other names:

FH Mexico-1

HGVS:

NC_000019.10:g.11110664G>A
NG_009060.1:g.26284G>A
NM_000527.5:c.953G>AMANE SELECT
NM_001195798.2:c.953G>A
NM_001195799.2:c.830G>A
NM_001195800.2:c.449G>A
NM_001195803.2:c.572G>A
NP_000518.1:p.Cys318Tyr
NP_000518.1:p.Cys318Tyr
NP_001182727.1:p.Cys318Tyr
NP_001182728.1:p.Cys277Tyr
NP_001182729.1:p.Cys150Tyr
NP_001182732.1:p.Cys191Tyr
LRG_274t1:c.953G>A
LRG_274:g.26284G>A
LRG_274p1:p.Cys318Tyr
NC_000019.9:g.11221340G>A
NM_000527.4:c.953G>A
P01130:p.Cys318Tyr
c.953G>A

Protein change:

C150Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001884; UniProtKB: P01130#VAR_005359; dbSNP: rs879254739

NCBI 1000 Genomes Browser:

rs879254739

Molecular consequence:

NM_000527.5:c.953G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.953G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.830G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.449G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.572G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003912563	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 1301956, 23375686 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003912563

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

Details of each submission

From Ambry Genetics, SCV003912563.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.C318Y variant (also known as c.953G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 953. The cysteine at codon 318 is replaced by tyrosine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This alteration, which is also known as p.C297Y, has been reported in individuals with FH and was found to have reduced LDLR activity at 2-5% (Hobbs HH et al. Hum Mutat, 1992;1:445-66; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). Another alteration at the same codon, p.C318F (c.953G>T), has been observed to segregate with disease in numerous unrelated Italian FH families (Lelli N et al. Hum. Genet. 1994;93(5):538-40, Mozas P et al. Hum. Mutat. 2004;24(2):187, Bertolini S et al. Atherosclerosis 2013;227(2):342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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