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NM_000527.5(LDLR):c.1072T>G (p.Cys358Gly) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 28, 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:
RCV002423856.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1072T>G (p.Cys358Gly)]

NM_000527.5(LDLR):c.1072T>G (p.Cys358Gly)

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.1072T>G (p.Cys358Gly)
HGVS:
  • NC_000019.10:g.11111525T>G
  • NG_009060.1:g.27145T>G
  • NM_000527.5:c.1072T>GMANE SELECT
  • NM_001195798.2:c.1072T>G
  • NM_001195799.2:c.949T>G
  • NM_001195800.2:c.568T>G
  • NM_001195803.2:c.691T>G
  • NP_000518.1:p.Cys358Gly
  • NP_000518.1:p.Cys358Gly
  • NP_001182727.1:p.Cys358Gly
  • NP_001182728.1:p.Cys317Gly
  • NP_001182729.1:p.Cys190Gly
  • NP_001182732.1:p.Cys231Gly
  • LRG_274t1:c.1072T>G
  • LRG_274:g.27145T>G
  • LRG_274p1:p.Cys358Gly
  • NC_000019.9:g.11222201T>G
  • NM_000527.4:c.1072T>G
Protein change:
C190G
Molecular consequence:
  • NM_000527.5:c.1072T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1072T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.949T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.568T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.691T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002718579Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Oct 28, 2022) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Ambry Genetics, SCV002718579.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.C358G variant (also known as c.1072T>G), located in coding exon 8 of the LDLR gene, results from a T to G substitution at nucleotide position 1072. The cysteine at codon 358 is replaced by glycine, 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). Another alteration at the same codon, p.C358Y (c.1073G>A), has been reported in association with FH (Humphries SE et al. J Med Genet, 2006 Dec;43:943-9). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the EGF-like 2 domain (Ambry internal data). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024