NM_000527.5(LDLR):c.1864G>C (p.Asp622His) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 9, 2023
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:: RCV003741993.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1864G>C (p.Asp622His)]

NM_000527.5(LDLR):c.1864G>C (p.Asp622His)

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.1864G>C (p.Asp622His)

HGVS:

NC_000019.10:g.11120110G>C
NG_009060.1:g.35730G>C
NM_000527.5:c.1864G>CMANE SELECT
NM_001195798.2:c.1864G>C
NM_001195799.2:c.1741G>C
NM_001195800.2:c.1360G>C
NM_001195803.2:c.1483G>C
NP_000518.1:p.Asp622His
NP_000518.1:p.Asp622His
NP_001182727.1:p.Asp622His
NP_001182728.1:p.Asp581His
NP_001182729.1:p.Asp454His
NP_001182732.1:p.Asp495His
LRG_274t1:c.1864G>C
LRG_274:g.35730G>C
LRG_274p1:p.Asp622His
NC_000019.9:g.11230786G>C
NM_000527.4:c.1864G>C

Protein change:

D454H

Molecular consequence:

NM_000527.5:c.1864G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1864G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1741G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1360G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1483G>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
SCV004433358	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 9, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15701167, 22698793, 27824480, 28645073, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004433358

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 9, 2023)

germline

clinical testing

PubMed (5)
[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

Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia.

Zakharova FM, Damgaard D, Mandelshtam MY, Golubkov VI, Nissen PH, Nilsen GG, Stenderup A, Lipovetsky BM, Konstantinov VO, Denisenko AD, Vasilyev VB, Faergeman O.

BMC Med Genet. 2005 Feb 8;6:6.

PubMed [citation]

PMID:: 15701167
PMCID:: PMC551615

The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.

Tichý L, Freiberger T, Zapletalová P, Soška V, Ravčuková B, Fajkusová L.

Atherosclerosis. 2012 Aug;223(2):401-8. doi: 10.1016/j.atherosclerosis.2012.05.014. Epub 2012 May 23.

PubMed [citation]

PMID:: 22698793

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004433358.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 622 of the LDLR protein (p.Asp622His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. 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. This variant disrupts the p.Asp622 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15701167, 22698793, 27824480, 28645073; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 29, 2024

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