NM_000527.5(LDLR):c.1514G>A (p.Gly505Asp) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 14, 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:: RCV003479080.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1514G>A (p.Gly505Asp)]

NM_000527.5(LDLR):c.1514G>A (p.Gly505Asp)

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.1514G>A (p.Gly505Asp)

HGVS:

NC_000019.10:g.11113690G>A
NG_009060.1:g.29310G>A
NM_000527.5:c.1514G>AMANE SELECT
NM_001195798.2:c.1514G>A
NM_001195799.2:c.1391G>A
NM_001195800.2:c.1010G>A
NM_001195803.2:c.1133G>A
NP_000518.1:p.Gly505Asp
NP_001182727.1:p.Gly505Asp
NP_001182728.1:p.Gly464Asp
NP_001182729.1:p.Gly337Asp
NP_001182732.1:p.Gly378Asp
LRG_274:g.29310G>A
NC_000019.9:g.11224366G>A
c.1514G>A

Protein change:

G337D

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001014; dbSNP: rs879254926

NCBI 1000 Genomes Browser:

rs879254926

Molecular consequence:

NM_000527.5:c.1514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1391G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1010G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1133G>A - 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
SCV004223789	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12052488, 31371270, 24785115 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004223789

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Nov 14, 2023)

germline

clinical testing

PubMed (3)
[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

Genetic characterization of Swedish patients with familial hypercholesterolemia: a heterogeneous pattern of mutations in the LDL receptor gene.

Lind S, Rystedt E, Eriksson M, Wiklund O, Angelin B, Eggertsen G.

Atherosclerosis. 2002 Aug;163(2):399-407.

PubMed [citation]

PMID:: 12052488

Individuals with familial hypercholesterolemia and cardiovascular events have higher circulating Lp(a) levels.

Pavanello C, Pirazzi C, Bjorkman K, Sandstedt J, Tarlarini C, Mosca L, Romeo S, Calabresi L, Mancina RM.

J Clin Lipidol. 2019 Sep - Oct;13(5):778-787.e6. doi: 10.1016/j.jacl.2019.06.011. Epub 2019 Jul 4.

PubMed [citation]

PMID:: 31371270

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004223789.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: LDLR c.1514G>A (p.Gly505Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251454 control chromosomes. c.1514G>A has been reported in the literature in individuals homozygous and heterozygous individuals affected with Familial Hypercholesterolemia (Lind_2002, Maglio_2014, Pavanello_2019). While both heterozygous and homozygous individuals displayed features including high cholesterol and cardiovascular disease, only some homozygotes had the full phenotype including Tendon xanthomas, leading authors to speculate the variant may result in a milder phenotype. Because of the presence of phenocopies in these patients with milder disease, this data cannot provide unequivocal conclusions about pathogenicity. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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 1, 2024

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