NM_000527.5(LDLR):c.502G>C (p.Asp168His) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 5, 2020
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:: RCV002338782.2

Allele description [Variation Report for NM_000527.5(LDLR):c.502G>C (p.Asp168His)]

NM_000527.5(LDLR):c.502G>C (p.Asp168His)

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.502G>C (p.Asp168His)

Other names:

FH Sephardic

HGVS:

NC_000019.10:g.11105408G>C
NG_009060.1:g.21028G>C
NM_000527.5:c.502G>CMANE SELECT
NM_001195798.2:c.502G>C
NM_001195799.2:c.379G>C
NM_001195800.2:c.314-1984G>C
NM_001195803.2:c.314-1157G>C
NP_000518.1:p.Asp168His
NP_000518.1:p.Asp168His
NP_001182727.1:p.Asp168His
NP_001182728.1:p.Asp127His
LRG_274t1:c.502G>C
LRG_274:g.21028G>C
LRG_274p1:p.Asp168His
NC_000019.9:g.11216084G>C
NM_000527.4:c.502G>C
P01130:p.Asp168His
c.502G>C

Protein change:

D127H

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000065; UniProtKB: P01130#VAR_005321; dbSNP: rs200727689

NCBI 1000 Genomes Browser:

rs200727689

Molecular consequence:

NM_001195800.2:c.314-1984G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1157G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.502G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.502G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.379G>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
SCV002642996	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 5, 2020)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 15823276, 16250003, 20145306, 20828696, 24529145, 28104544, 31401775, 8462973, 8644729, 8882879, 9259195 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002642996

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 5, 2020)

germline

clinical testing

PubMed (11)
[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

The molecular basis of familial hypercholesterolaemia in Turkish patients.

Sözen MM, Whittall R, Oner C, Tokatli A, Kalkanoğlu HS, Dursun A, Coşkun T, Oner R, Humphries SE.

Atherosclerosis. 2005 May;180(1):63-71.

PubMed [citation]

PMID:: 15823276

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV002642996.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The p.D168H pathogenic mutation (also known as c.502G>C), located in coding exon 4 of the LDLR gene, results from a G to C substitution at nucleotide position 502. The aspartic acid at codon 168 is replaced by histidine, an amino acid with similar properties. This mutation was first reported (as legacy p.D147H) in multiple families from a Sephardic Jewish hypercholesterolemia cohort, including one family with segregation in multiple affected heterozygous and homozygous cases; in vitro functional studies in homozygous fibroblasts demonstrated significant impact on LDLR trafficking and LDL binding (Leitersdorf E et al. Hum. Genet., 1993 Mar;91:141-7). This mutation has also been reported in additional familial hypercholesterolemia (FH) cohorts (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8; Durst R et al. Atherosclerosis, 2017 02;257:55-63). In addition, alternate amino acid substitutions at this codon, p.D168Y, p.D168N, p.D168A, p.D168E, p.D168G, have also been reported in individuals with FH, indicating this position may be a hotspot location (Christiano AM et al. Am. J. Hum. Genet., 1996 Apr;58:671-81; Day IN et al. Hum. Mutat., 1997;10:116-27; Santos PC et al. Atherosclerosis, 2014 Mar;233:206-10; Sözen MM et al. Atherosclerosis, 2005 May;180:63-71; Chmara M et al. J. Appl. Genet., 2010;51:95-106). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: Feb 25, 2025

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