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NM_000527.5(LDLR):c.1073G>A (p.Cys358Tyr) AND Familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 19, 2024
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:
RCV001853402.5

Allele description [Variation Report for NM_000527.5(LDLR):c.1073G>A (p.Cys358Tyr)]

NM_000527.5(LDLR):c.1073G>A (p.Cys358Tyr)

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.1073G>A (p.Cys358Tyr)
HGVS:
  • NC_000019.10:g.11111526G>A
  • NG_009060.1:g.27146G>A
  • NM_000527.5:c.1073G>AMANE SELECT
  • NM_001195798.2:c.1073G>A
  • NM_001195799.2:c.950G>A
  • NM_001195800.2:c.569G>A
  • NM_001195803.2:c.692G>A
  • NP_000518.1:p.Cys358Tyr
  • NP_000518.1:p.Cys358Tyr
  • NP_001182727.1:p.Cys358Tyr
  • NP_001182728.1:p.Cys317Tyr
  • NP_001182729.1:p.Cys190Tyr
  • NP_001182732.1:p.Cys231Tyr
  • LRG_274t1:c.1073G>A
  • LRG_274:g.27146G>A
  • LRG_274p1:p.Cys358Tyr
  • NC_000019.9:g.11222202G>A
  • NM_000527.4:c.1073G>A
  • P01130:p.Cys358Tyr
  • c.1073G>A
Protein change:
C190Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000402; UniProtKB: P01130#VAR_062377; dbSNP: rs875989915
NCBI 1000 Genomes Browser:
rs875989915
Molecular consequence:
  • NM_000527.5:c.1073G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1073G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.950G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.569G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.692G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial hypercholesterolemia
Identifiers:
MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002246069Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 19, 2024) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.

Humphries SE, Whittall RA, Hubbart CS, Maplebeck S, Cooper JA, Soutar AK, Naoumova R, Thompson GR, Seed M, Durrington PN, Miller JP, Betteridge DJ, Neil HA; Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee.

J Med Genet. 2006 Dec;43(12):943-9. Erratum in: J Med Genet. 2009 Dec;46(12):861. J Med Genet. 2010 Dec;47(12):862.

PubMed [citation]
PMID:
17142622
PMCID:
PMC2563208

Increased intima-media thickness in carriers of the ldl-receptor defective gene versus noncarriers with newly detected asymptomatic severe hypercholesterolemia.

Vladimirova-Kitova LG, Deneva-Koicheva TI.

Echocardiography. 2011 Feb;28(2):223-34. doi: 10.1111/j.1540-8175.2010.01304.x.

PubMed [citation]
PMID:
21276076
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002246069.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 358 of the LDLR protein (p.Cys358Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17142622, 21276076). This variant is also known as p.C337Y. ClinVar contains an entry for this variant (Variation ID: 226346). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: May 16, 2025