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NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 24, 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:
RCV002444847.3

Allele description [Variation Report for NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr)]

NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr)

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.326G>A (p.Cys109Tyr)
Other names:
NP_000518.1:p.C109Y
HGVS:
  • NC_000019.10:g.11105232G>A
  • NG_009060.1:g.20852G>A
  • NM_000527.5:c.326G>AMANE SELECT
  • NM_001195798.2:c.326G>A
  • NM_001195799.2:c.203G>A
  • NM_001195800.2:c.314-2160G>A
  • NM_001195803.2:c.314-1333G>A
  • NP_000518.1:p.Cys109Tyr
  • NP_000518.1:p.Cys109Tyr
  • NP_001182727.1:p.Cys109Tyr
  • NP_001182728.1:p.Cys68Tyr
  • LRG_274t1:c.326G>A
  • LRG_274:g.20852G>A
  • LRG_274p1:p.Cys109Tyr
  • NC_000019.9:g.11215908G>A
  • NM_000527.4:c.326G>A
  • c.326G>A
Protein change:
C109Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000051; dbSNP: rs121908042
NCBI 1000 Genomes Browser:
rs121908042
Molecular consequence:
  • NM_001195800.2:c.314-2160G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1333G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.203G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002612497Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Apr 24, 2024) 		germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed
See all PubMed Citations (13)

Details of each submission

From Ambry Genetics, SCV002612497.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (13)

Description

The c.326G>A (p.C109Y) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 326, causing the cysteine (C) at amino acid position 109 to be replaced by a tyrosine (Y). Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/250250) total alleles studied. The highest observed frequency was 0.001% (1/112912) of European (non-Finnish) alleles. This alteration, which is also known at p.C88Y, has been reported in individuals with FH (Sun, 1998; Heath, 2001; Sozen, 2004; Taylor, 2007; Chmara, 2010; Hooper, 2012; Norsworthy, 2014; Do, 2015; Dron, 2020; Meshkov, 2021; Sturm, 2021; Leren, 2021). This amino acid position is highly conserved in available vertebrate species. 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) (Vill&eacute;ger, 2002). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 domain (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

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

Last Updated: Feb 25, 2025