VCV000250971.11 - ClinVar

NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)

Germline

Top reviewed classifications are shown here.

Submission summary:

6 submissions

6 submitters

3 conditions

Reviewed by expert panel

Uncertain significance

Apr 2022 by ClinGen Famili… FDA Recognized Database

for Hypercholesterolemia, familial, 1

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)

Variation ID: 250971 Accession: VCV000250971.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11089552 (GRCh38) [ NCBI UCSC ] 19: 11200228 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 13, 2017	May 1, 2024	Apr 29, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.4G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Gly2Arg	missense
NM_001195798.2:c.4G>C	NP_001182727.1:p.Gly2Arg	missense
NM_001195799.2:c.4G>C	NP_001182728.1:p.Gly2Arg	missense
NM_001195800.2:c.4G>C	NP_001182729.1:p.Gly2Arg	missense
NM_001195803.2:c.4G>C	NP_001182732.1:p.Gly2Arg	missense
NR_163945.1:n.108C>G		non-coding transcript variant
NC_000019.10:g.11089552G>C
NC_000019.9:g.11200228G>C
NG_009060.1:g.5172G>C
LRG_274:g.5172G>C
LRG_274t1:c.4G>C	LRG_274p1:p.Gly2Arg
	P01130:p.Gly2Arg

... more HGVS ... less HGVS

Protein change

G2R

Other names

NM_000527.5(LDLR):c.4G>C

Canonical SPDI

NC_000019.10:11089551:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA085719 LDLR-LOVD, British Heart Foundation: LDLR_001001 UniProtKB: P01130#VAR_011862 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LDLR		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4076	4352
LDLR-AS1	-	-	-	GRCh38	-	204

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hypercholesterolemia, familial, 1	Uncertain significance (3)	reviewed by expert panel	Apr 29, 2022	RCV000237142.5
Familial hypercholesterolemia	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 27, 2021	RCV001182216.8
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jan 17, 2024	RCV004020945.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Apr 29, 2022)	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2) Method: curation	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel FDA Recognized Database Accession: SCV002817168.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/610086db-97cc-4269-9e2d-65da8253257c Comment: NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 and PP4 as defined by the ClinGen … (more) NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 and PP4 as defined by the ClinGen Familial NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00016 (0.016%) in African exomes (gnomAD v2.1.1). PP4 - Variant meets PM2 and is identified in one index cases who fulfills SB criteria for FH (1 case from CGMC, UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)). (less)
Likely benign (Mar 25, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: literature only	Familial hypercholesterolemia Affected status: yes Allele origin: germline	LDLR-LOVD, British Heart Foundation Accession: SCV000294410.2 First in ClinVar: Jul 29, 2016 Last updated: Aug 13, 2017	Publications: PubMed (1) PubMed: 11933210 Number of individuals with the variant: 1
Uncertain significance (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: HipercolBrasil Accession: SCV000588479.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017	Comment on evidence: %MAF(ExAC):0.001731
Likely benign (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001347575.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020
Uncertain significance (Aug 27, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002225591.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 11933210‚ 25461735 Comment: This sequence change replaces glycine with arginine at codon 2 of the LDLR protein (p.Gly2Arg). The glycine residue is weakly conserved and there is a … (more) This sequence change replaces glycine with arginine at codon 2 of the LDLR protein (p.Gly2Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs5931, ExAC 0.02%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 11933210, 25461735). ClinVar contains an entry for this variant (Variation ID: 250971). 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. 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. (less)
Uncertain significance (Jan 17, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005035888.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 11472756‚ 11933210‚ 16250003‚ 25461735‚ 33519890 Comment: The p.G2R variant (also known as c.4G>C), located in coding exon 1 of the LDLR gene, results from a G to C substitution at nucleotide … (more) The p.G2R variant (also known as c.4G>C), located in coding exon 1 of the LDLR gene, results from a G to C substitution at nucleotide position 4. The glycine at codon 2 is replaced by arginine, an amino acid with dissimilar properties. This variant and a different nucleotide substitution resulting in the same amino acid change (c.4G>A) have been detected in individuals from familial hypercholesterolemia cohorts (Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Salazar LA et al. Hum Mutat, 2002 Apr;19:462-3; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6). This amino acid position is not well conserved in available vertebrate species and arginine is the reference amino acid in many other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)

Comment:

NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 and PP4 as defined by the ClinGen Familial NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00016 (0.016%) in African exomes (gnomAD v2.1.1). PP4 - Variant meets PM2 and is identified in one index cases who fulfills SB criteria for FH (1 case from CGMC, UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)).

Comment:

This sequence change replaces glycine with arginine at codon 2 of the LDLR protein (p.Gly2Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs5931, ExAC 0.02%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 11933210, 25461735). ClinVar contains an entry for this variant (Variation ID: 250971). 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. 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.

Comment:

The p.G2R variant (also known as c.4G>C), located in coding exon 1 of the LDLR gene, results from a G to C substitution at nucleotide position 4. The glycine at codon 2 is replaced by arginine, an amino acid with dissimilar properties. This variant and a different nucleotide substitution resulting in the same amino acid change (c.4G>A) have been detected in individuals from familial hypercholesterolemia cohorts (Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Salazar LA et al. Hum Mutat, 2002 Apr;19:462-3; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6). This amino acid position is not well conserved in available vertebrate species and arginine is the reference amino acid in many other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype-Phenotype Correlations of the Disease.	Kamar A	Frontiers in genetics	2021	PMID: 33519890
Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects.	Jannes CE	Atherosclerosis	2015	PMID: 25461735
Update of the molecular basis of familial hypercholesterolemia in The Netherlands.	Fouchier SW	Human mutation	2005	PMID: 16250003
Molecular basis of familial hypercholesterolemia in Brazil: Identification of seven novel LDLR gene mutations.	Salazar LA	Human mutation	2002	PMID: 11933210
A novel splice-site mutation in intron 7 causes more severe hypercholesterolemia than a combined FH-FDB defect.	deCampo A	Atherosclerosis	2001	PMID: 11472756
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/610086db-97cc-4269-9e2d-65da8253257c	-	-	-	-

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...