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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 24, 2022
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:: RCV001071431.9

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:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001236737	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 24, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 9259195, 9678702, 12124988, 15556094, 16205024, 19007590, 8462973, 16250003, 20828696, 28104544, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001236737

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 24, 2022)

germline

clinical testing

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

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

Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia.

Day IN, Whittall RA, O'Dell SD, Haddad L, Bolla MK, Gudnason V, Humphries SE.

Hum Mutat. 1997;10(2):116-27.

PubMed [citation]

PMID:: 9259195

Identification of a common low density lipoprotein receptor mutation (C163Y) in the west of Scotland.

Lee WK, Haddad L, Macleod MJ, Dorrance AM, Wilson DJ, Gaffney D, Dominiczak MH, Packard CJ, Day IN, Humphries SE, Dominiczak AF.

J Med Genet. 1998 Jul;35(7):573-8.

PubMed [citation]

PMID:: 9678702
PMCID:: PMC1051368

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001236737.6

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

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 168 of the LDLR protein (p.Asp168His). Experimental studies have shown that this missense change affects LDLR function (PMID: 8462973). This variant disrupts the p.Asp168 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9259195, 9678702, 12124988, 15556094, 16205024, 19007590). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251258). This variant is also known as p.D147H and FH-Sephardic. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 8462973, 16250003, 20828696, 28104544). It has also been observed to segregate with disease in related individuals.

#	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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