NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 30, 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:: RCV002399654.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)]

NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)

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.1747C>T (p.His583Tyr)

Other names:

p.H583Y:CAC>TAC; NP_000518.1:p.H583Y

HGVS:

NC_000019.10:g.11116900C>T
NG_009060.1:g.32520C>T
NM_000527.5:c.1747C>TMANE SELECT
NM_001195798.2:c.1747C>T
NM_001195799.2:c.1624C>T
NM_001195800.2:c.1243C>T
NM_001195803.2:c.1366C>T
NP_000518.1:p.His583Tyr
NP_000518.1:p.His583Tyr
NP_001182727.1:p.His583Tyr
NP_001182728.1:p.His542Tyr
NP_001182729.1:p.His415Tyr
NP_001182732.1:p.His456Tyr
LRG_274t1:c.1747C>T
LRG_274:g.32520C>T
LRG_274p1:p.His583Tyr
NC_000019.9:g.11227576C>T
NM_000527.4:c.1747C>T
c.1747C>T

Protein change:

H415Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000234; dbSNP: rs730882109

NCBI 1000 Genomes Browser:

rs730882109

Molecular consequence:

NM_000527.5:c.1747C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1747C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1624C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1243C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1366C>T - 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
SCV002711608	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 30, 2024)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 7903864, 19318025, 20538126, 21376320, 22353362, 22698793, 22883975, 23155708, 23375686, 25846081, 27206935, 28028493, 28475941, 29233637, 29399563, 32331935, 32800790, 36011335, 37805670 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002711608

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 30, 2024)

germline

clinical testing

PubMed (19)
[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

Familial hypercholesterolemia in China. Identification of mutations in the LDL-receptor gene that result in a receptor-negative phenotype.

Sun XM, Patel DD, Webb JC, Knight BL, Fan LM, Cai HJ, Soutar AK.

Arterioscler Thromb. 1994 Jan;14(1):85-94.

PubMed [citation]

PMID:: 7903864

Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318025

See all PubMed Citations (19)

Details of each submission

From Ambry Genetics, SCV002711608.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

The c.1747C>T (p.H583Y) alteration is located in exon 12 (coding exon 12) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 1747, causing the histidine (H) at amino acid position 583 to be replaced by a tyrosine (Y). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (29/282882) total alleles studied. The highest observed frequency was 0.12% (24/19952) of East Asian alleles. This alteration (also described as legacy p.H562Y) has been described as a Taiwanese and Chinese founder mutation and has been reported in the heterozygous state, and in conjunction with another alteration in LDLR, in multiple individuals with familial hypercholesterolemia (FH) and has been reported to segregate with disease in several families (Lee, 2023; Tada, 2020; Kim, 2018; Du, 2016; Fan, 2015; Chiou, 2011; Chiou, 2010; Rutkowska, 2022; Sreedharan, 2020; Ma, 2018; Yao, 2012; Sun, 1994; Chiou, 2012). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as 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: Aug 11, 2024

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