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NM_000527.5(LDLR):c.311G>A (p.Cys104Tyr) AND Familial hypercholesterolemia

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jan 4, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001046101.8

Allele description [Variation Report for NM_000527.5(LDLR):c.311G>A (p.Cys104Tyr)]

NM_000527.5(LDLR):c.311G>A (p.Cys104Tyr)

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.311G>A (p.Cys104Tyr)
HGVS:
  • NC_000019.10:g.11102784G>A
  • NG_009060.1:g.18404G>A
  • NM_000527.5:c.311G>AMANE SELECT
  • NM_001195798.2:c.311G>A
  • NM_001195799.2:c.191-2436G>A
  • NM_001195800.2:c.311G>A
  • NM_001195803.2:c.311G>A
  • NP_000518.1:p.Cys104Tyr
  • NP_000518.1:p.Cys104Tyr
  • NP_001182727.1:p.Cys104Tyr
  • NP_001182729.1:p.Cys104Tyr
  • NP_001182732.1:p.Cys104Tyr
  • LRG_274t1:c.311G>A
  • LRG_274:g.18404G>A
  • LRG_274p1:p.Cys104Tyr
  • NC_000019.9:g.11213460G>A
  • NM_000527.4:c.311G>A
  • c.311G>A
Protein change:
C104Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001117; dbSNP: rs875989895
NCBI 1000 Genomes Browser:
rs875989895
Molecular consequence:
  • NM_001195799.2:c.191-2436G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.311G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.311G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.311G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.311G>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
SCV001209989Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 4, 2024) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001482199Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Feb 1, 2021) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain.

Bieri S, Djordjevic JT, Daly NL, Smith R, Kroon PA.

Biochemistry. 1995 Oct 10;34(40):13059-65.

PubMed [citation]
PMID:
7548065

Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.

Daly NL, Scanlon MJ, Djordjevic JT, Kroon PA, Smith R.

Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6334-8.

PubMed [citation]
PMID:
7603991
PMCID:
PMC41512
See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001209989.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 104 of the LDLR protein (p.Cys104Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 15359125, 22883975; Invitae). This variant is also known as C83Y. ClinVar contains an entry for this variant (Variation ID: 226315). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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). This variant disrupts the p.Cys104 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11313767; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001482199.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: LDLR c.311G>A (p.Cys104Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes. c.311G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Kim_2004, Hooper_2012, Kusters_2013). These data indicate that the variant is likely to be associated with disease. The C104 residue is one of the cysteines forming intra-repeat disulfide bonds in repeat 2 of the ApoB-binding domain (Hobbs et al., 1990), indicating structural importance to codon 104. Additionally, several other variants at codon 104 have been reported in association with hypercholesterolemia (C104R, C104F, C104W; HGMD). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 29, 2024