NM_000527.5(LDLR):c.1004G>T (p.Gly335Val) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 21, 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:: RCV002519844.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1004G>T (p.Gly335Val)]

NM_000527.5(LDLR):c.1004G>T (p.Gly335Val)

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.1004G>T (p.Gly335Val)

Other names:

NM_000527.5(LDLR):c.1004G>T; p.Gly335Val

HGVS:

NC_000019.10:g.11110715G>T
NG_009060.1:g.26335G>T
NM_000527.5:c.1004G>TMANE SELECT
NM_001195798.2:c.1004G>T
NM_001195799.2:c.881G>T
NM_001195800.2:c.500G>T
NM_001195803.2:c.623G>T
NP_000518.1:p.Gly335Val
NP_000518.1:p.Gly335Val
NP_001182727.1:p.Gly335Val
NP_001182728.1:p.Gly294Val
NP_001182729.1:p.Gly167Val
NP_001182732.1:p.Gly208Val
LRG_274t1:c.1004G>T
LRG_274:g.26335G>T
LRG_274p1:p.Gly335Val
NC_000019.9:g.11221391G>T
NM_000527.4:c.1004G>T
c.1004G>T

Protein change:

G167V

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000335; dbSNP: rs869320650

NCBI 1000 Genomes Browser:

rs869320650

Molecular consequence:

NM_000527.5:c.1004G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1004G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.881G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.500G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.623G>T - 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
SCV003443159	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 21, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1301956, 11668627, 15556094, 23375686, 27765764, 28502510, 10735632, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003443159

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 21, 2022)

germline

clinical testing

PubMed (8)
[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

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent.

Wang J, Huff E, Janecka L, Hegele RA.

Hum Mutat. 2001 Oct;18(4):359.

PubMed [citation]

PMID:: 11668627

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443159.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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. 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. This variant disrupts the p.Gly335 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11668627, 15556094, 23375686, 27765764, 28502510). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 251587). This variant is also known as G314V. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10735632). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 335 of the LDLR protein (p.Gly335Val).

#	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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