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NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys) AND LDLR-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 22, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV003407739.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys)]

NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys)

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.1897C>T (p.Arg633Cys)
Other names:
NP_000518.1:p.R633C
HGVS:
  • NC_000019.10:g.11120143C>T
  • NG_009060.1:g.35763C>T
  • NM_000527.5:c.1897C>TMANE SELECT
  • NM_001195798.2:c.1897C>T
  • NM_001195799.2:c.1774C>T
  • NM_001195800.2:c.1393C>T
  • NM_001195803.2:c.1516C>T
  • NP_000518.1:p.Arg633Cys
  • NP_000518.1:p.Arg633Cys
  • NP_001182727.1:p.Arg633Cys
  • NP_001182728.1:p.Arg592Cys
  • NP_001182729.1:p.Arg465Cys
  • NP_001182732.1:p.Arg506Cys
  • LRG_274t1:c.1897C>T
  • LRG_274:g.35763C>T
  • LRG_274p1:p.Arg633Cys
  • NC_000019.9:g.11230819C>T
  • NM_000527.4:c.1897C>T
  • NM_000527.5:c.1897C>T
  • P01130:p.Arg633Cys
  • c.1897C>T
Protein change:
R465C
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001544; UniProtKB: P01130#VAR_005405
Molecular consequence:
  • NM_000527.5:c.1897C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1897C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1774C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1393C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1516C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
LDLR-related disorder
Synonyms:
LDLR-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004113889PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Jul 22, 2024) 		germlineclinical testing

Help

Summary from all submissions

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

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004113889.2

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

Description

The LDLR c.1897C>T variant is predicted to result in the amino acid substitution p.Arg633Cys. This variant (also reported as c.Arg612Cys in the literature) has been reported in many unrelated individuals with familial hypercholesterolemia (Mozas et al. 2004. PubMed ID: 15241806; Chiou et al. 2011. PubMed ID: 21376320; Tichý et al. 2012. PubMed ID: 22698793; Day et al. 1997. PubMed ID: 9259195, referred to as R612C; Bertolini et al. 2013. PubMed ID: 23375686, supplementary data; Di Taranto et al. 2019. PubMed ID: 30710474, supplementary data; Dron et al. 2020. PubMed ID: 32041611; Sturm et al. 2021. PubMed ID: 34037665, supplementary data; Futema et al. 2017. PubMed ID: 28349888). In vitro analysis of this variant indicated that this variant results in diminished LDLR expression and activity (Galicia-Garcia et al. 2020. PubMed ID: 32015373). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant has been reported in ClinVar by many outside laboratories as likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/226379/). Two other amino acid substitutions at this position (p.Arg633His and p.Arg633Leu) have also been reported in individuals with hypercholesterolemia (Fouchier et al. 2005. PubMed ID: 16250003; Di Taranto et al. 2021. PubMed ID: 34297352). In summary, we categorize c.1897C>T (p.Arg633Cys) as pathogenic.

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

Last Updated: Oct 13, 2024