NM_000527.5(LDLR):c.940G>A (p.Gly314Arg) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 6, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001185251.8

Allele description [Variation Report for NM_000527.5(LDLR):c.940G>A (p.Gly314Arg)]

NM_000527.5(LDLR):c.940G>A (p.Gly314Arg)

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.940G>A (p.Gly314Arg)

HGVS:

NC_000019.10:g.11107514G>A
NG_009060.1:g.23134G>A
NM_000527.5:c.940G>AMANE SELECT
NM_001195798.2:c.940G>A
NM_001195799.2:c.817G>A
NM_001195800.2:c.436G>A
NM_001195803.2:c.559G>A
NP_000518.1:p.Gly314Arg
NP_000518.1:p.Gly314Arg
NP_001182727.1:p.Gly314Arg
NP_001182728.1:p.Gly273Arg
NP_001182729.1:p.Gly146Arg
NP_001182732.1:p.Gly187Arg
LRG_274t1:c.940G>A
LRG_274:g.23134G>A
LRG_274p1:p.Gly314Arg
NC_000019.9:g.11218190G>A
NM_000527.4:c.940G>A
c.940G>A

Protein change:

G146R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000695; dbSNP: rs72658858

NCBI 1000 Genomes Browser:

rs72658858

Molecular consequence:

NM_000527.5:c.940G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.940G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.817G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.436G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

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
SCV001351424	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17347910, 33794673, 25741868
SCV001460260	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV003259699	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 30, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17347910, 28104544, 28349888, 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001351424

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 6, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001460260

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 16, 2020)

germline

clinical testing

SCV003259699

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 30, 2022)

germline

clinical testing

PubMed (6)
[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

The Spectrum of Low-Density Lipoprotein Receptor Mutations in a Large Turkish Cohort of Patients with Familial Hypercholesterolemia.

Turkyilmaz A, Kurnaz E, Alavanda C, Yarali O, Kartal Baykan E, Yavuz D, Cayir A, Ata P.

Metab Syndr Relat Disord. 2021 Aug;19(6):340-346. doi: 10.1089/met.2021.0004. Epub 2021 Apr 1.

PubMed [citation]

PMID:: 33794673

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (8)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001351424.4

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

Description

This missense variant (also known as p.Gly293Arg in the mature protein) replaces glycine with arginine at codon 314 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown the mutant protein to show normal protein maturation and plasma membrane localization (Khalid Jawabri 2020, dissertation, United Arab Emirates University). This variant has been reported in several individuals affected with premature atherosclerosis and/or familial hypercholesterolemia in the literature (PMID: 17347910, 33794673). This variant has been identified in 13/282176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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

From Natera, Inc., SCV001460260.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003259699.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 314 of the LDLR protein (p.Gly314Arg). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs72658858, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17347910, 28104544, 28349888). This variant is also known as G293R. ClinVar contains an entry for this variant (Variation ID: 183102). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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