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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002642996Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Oct 5, 2020) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

Last Updated: May 1, 2024