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NM_000527.5(LDLR):c.2001T>G (p.Cys667Trp) AND LDLR-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 16, 2023
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:
RCV003417848.4

Allele description [Variation Report for NM_000527.5(LDLR):c.2001T>G (p.Cys667Trp)]

NM_000527.5(LDLR):c.2001T>G (p.Cys667Trp)

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.2001T>G (p.Cys667Trp)
HGVS:
  • NC_000019.10:g.11120383T>G
  • NG_009060.1:g.36003T>G
  • NM_000527.5:c.2001T>GMANE SELECT
  • NM_001195798.2:c.2001T>G
  • NM_001195799.2:c.1878T>G
  • NM_001195800.2:c.1497T>G
  • NM_001195803.2:c.1606+150T>G
  • NP_000518.1:p.Cys667Trp
  • NP_000518.1:p.Cys667Trp
  • NP_001182727.1:p.Cys667Trp
  • NP_001182728.1:p.Cys626Trp
  • NP_001182729.1:p.Cys499Trp
  • LRG_274t1:c.2001T>G
  • LRG_274:g.36003T>G
  • LRG_274p1:p.Cys667Trp
  • NC_000019.9:g.11231059T>G
  • NM_000527.4:c.2001T>G
  • c.2001T>G
Protein change:
C499W
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001582; dbSNP: rs879255109
NCBI 1000 Genomes Browser:
rs879255109
Molecular consequence:
  • NM_001195803.2:c.1606+150T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.2001T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.2001T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1878T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1497T>G - 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
SCV004107569PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jun 16, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004107569.1

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

Description

The LDLR c.2001T>G variant is predicted to result in the amino acid substitution p.Cys667Trp. This variant, also known as Cys646Trp using legacy nomenclature, was reported in an individual with hypercholesterolemia (Patient C4 in Nissen et al 1998. PubMed ID: 9727746). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, several other missense variant impacting the same amino acid (p.Cys667Ser, p.Cys667Arg, p.Cys667Tyr and p.Cys667Phe) have been reported in patients with hypercholesterolemia (Zakharova et al. 2005. PubMed ID: 15701167; Vergopoulos et al. 1997. PubMed ID: 9412789; Leitersdorf. 1990. PubMed ID: 2318961; Heath et al. 2001. PubMed ID: 11313767). Based on this evidence, we interpret the c.2001T>G (p.Cys667Trp) variant as pathogenic.

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

Last Updated: Jun 23, 2024