NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 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:: RCV002415887.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1955T>C (p.Met652Thr)]

NM_000527.5(LDLR):c.1955T>C (p.Met652Thr)

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.1955T>C (p.Met652Thr)

Other names:

NM_000527.5(LDLR):c.1955T>C

HGVS:

NC_000019.10:g.11120201T>C
NG_009060.1:g.35821T>C
NM_000527.5:c.1955T>CMANE SELECT
NM_001195798.2:c.1955T>C
NM_001195799.2:c.1832T>C
NM_001195800.2:c.1451T>C
NM_001195803.2:c.1574T>C
NP_000518.1:p.Met652Thr
NP_000518.1:p.Met652Thr
NP_001182727.1:p.Met652Thr
NP_001182728.1:p.Met611Thr
NP_001182729.1:p.Met484Thr
NP_001182732.1:p.Met525Thr
LRG_274t1:c.1955T>C
LRG_274:g.35821T>C
LRG_274p1:p.Met652Thr
NC_000019.9:g.11230877T>C
NM_000527.4:c.1955T>C
c.1955T>C

Protein change:

M484T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000266; dbSNP: rs875989936

NCBI 1000 Genomes Browser:

rs875989936

Molecular consequence:

NM_000527.5:c.1955T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1955T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1832T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1451T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1574T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002718365	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 19, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20236128, 20809525, 22883975, 28964736, 33418990, 34040191, 34869944 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002718365

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 19, 2024)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project.

Taylor A, Wang D, Patel K, Whittall R, Wood G, Farrer M, Neely RD, Fairgrieve S, Nair D, Barbir M, Jones JL, Egan S, Everdale R, Lolin Y, Hughes E, Cooper JA, Hadfield SG, Norbury G, Humphries SE.

Clin Genet. 2010 Jun;77(6):572-80. doi: 10.1111/j.1399-0004.2009.01356.x. Epub 2010 Mar 13.

PubMed [citation]

PMID:: 20236128

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002718365.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.M652T variant (also known as c.1955T>C), located in coding exon 13 of the LDLR gene, results from a T to C substitution at nucleotide position 1955. The methionine at codon 652 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH) (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Taylor A et al. Clin Genet, 2010 Jun;77:572-80; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Defesche JC et al. J Clin Lipidol, 2017 Sep;11:1338-1346.e7; Ajufo E et al. Genet Med, 2021 Sep;23:1697-1704). (Meshkov A et al. Genes (Basel), 2021 Jan;12; Ambry internal data). Internal structural analysis indicates this variant to be structurally disruptive (Rudenko G et al. Science. 2002 Dec;298(5602):2353-8). Additionally, an in vitro assay showed this alteration had a reduction of LDL uptake (Larrea-Sebal A et al. JACC Basic Transl Sci, 2021 Nov;6:815-827). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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