VCV000252262.45 - ClinVar

NM_000527.5(LDLR):c.2232A>G (p.Arg744=)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Benign

15 out of 20 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.2232A>G (p.Arg744=)

Variation ID: 252262 Accession: VCV000252262.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11123265 (GRCh38) [ NCBI UCSC ] 19: 11233941 (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	Oct 2, 2016	May 3, 2025	Apr 9, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.2232A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Arg744=	synonymous
NM_001195798.2:c.2232A>G	NP_001182727.1:p.Arg744=	synonymous
NM_001195799.2:c.2109A>G	NP_001182728.1:p.Arg703=	synonymous
NM_001195800.2:c.1728A>G	NP_001182729.1:p.Arg576=	synonymous
NM_001195803.2:c.1698A>G	NP_001182732.1:p.Arg566=	synonymous
NC_000019.10:g.11123265A>G
NC_000019.9:g.11233941A>G
NG_009060.1:g.38885A>G
LRG_274:g.38885A>G
LRG_274t1:c.2232A>G	LRG_274p1:p.Arg744=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000019.10:11123264:A:G

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.

0.21985 (A)

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

The Genome Aggregation Database (gnomAD) 0.75108

Exome Aggregation Consortium (ExAC) 0.77621

1000 Genomes Project 30x 0.77733

The Genome Aggregation Database (gnomAD), exomes 0.78115

1000 Genomes Project 0.78015

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.73874

The Genome Aggregation Database (gnomAD) 0.74675

Trans-Omics for Precision Medicine (TOPMed) 0.75439

The Genome Aggregation Database (gnomAD), exomes 0.76113

Links

ClinGen: CA039203 LDLR-LOVD, British Heart Foundation: LDLR_001618 dbSNP: rs5927 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	4374	4691

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	Benign (7)	criteria provided, multiple submitters, no conflicts	Jun 10, 2021	RCV000238103.24
not specified	Benign (6)	criteria provided, multiple submitters, no conflicts	Apr 9, 2025	RCV000252146.23
Familial hypercholesterolemia	Benign (4)	criteria provided, multiple submitters, no conflicts	Feb 4, 2025	RCV001275783.20
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Nov 30, 2024	RCV001812664.20
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 8, 2015	RCV002418074.9

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.	Expand all rows Collapse all rows 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.
Benign (Mar 25, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013)	Familial hypercholesterolemia	LDLR-LOVD, British Heart Foundation Accession: SCV000295923.2 First in ClinVar: Jul 29, 2016 Last updated: May 03, 2018	Publications: PubMed (1) PubMed: 24373485 Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes more Observation 1 Collection method: literature only Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	NOT SPECIFIED	PreventionGenetics, part of Exact Sciences Accession: SCV000304691.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Mar 01, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial hypercholesterolemia	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000323005.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Comment: show 54 Hmz + 75 Htz / 135 non-FH individuals; MAF = 29,1% in 86 Spanish healthy individuals (less) Observation: 2 Observation 1 Collection method: research Allele origin: germline Affected status: yes Comment on evidence: %MAF (ExAC):22.38 Observation 2 Collection method: research Allele origin: germline Affected status: yes

Benign (Sep 28, 2016) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not specified	GeneDx Accession: SCV000524334.4 First in ClinVar: Mar 08, 2017 Last updated: Apr 09, 2018	Comment: show This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Nov 14, 2017) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711400.2 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: show Arg744Arg in exon 15 of LDLR: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 31.3% (1377/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs5927). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

Benign (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Hypercholesterolemia, familial, 1	Illumina Laboratory Services, Illumina Accession: SCV000410543.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Apr 05, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Chora et al. (Genet Med. 2022))	Familial hypercholesterolemia	GENinCode PLC Accession: SCV005073997.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Autosomal dominant inheritance)	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005312110.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Observation: 1 Collection method: not provided Allele origin: germline Affected status: yes Observation 1 Collection method: not provided Allele origin: germline Affected status: yes

Benign (Feb 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial hypercholesterolemia	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001717062.5 First in ClinVar: Jun 15, 2021 Last updated: Feb 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Nov 30, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	not provided	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002049746.7 First in ClinVar: Jan 08, 2022 Last updated: Mar 11, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Jun 10, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypercholesterolemia, familial, 1	Genome-Nilou Lab Accession: SCV001738025.2 First in ClinVar: Jun 24, 2021 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Sex: mixed

Benign (Jun 11, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypercholesterolemia, familial, 1	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen Accession: SCV000987010.1 First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019	Comment: show Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), this variant is classified as benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Jun 01, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial hypercholesterolemia	Color Diagnostics, LLC DBA Color Health Accession: SCV000689775.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Benign (Dec 08, 2015) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002725408.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: show This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Apr 09, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV006067246.1 First in ClinVar: May 03, 2025 Last updated: May 03, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	Familial hypercholesterolemia	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000606617.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Benign (Sep 16, 2020) N Not contributing to aggregate classification	no assertion criteria provided	Familial hypercholesterolemia	Natera, Inc. Accession: SCV001461329.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740479.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001926076.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Feb 09, 2023) N Not contributing to aggregate classification	no assertion criteria provided (ACMG Guidelines, 2015)	Familial hypercholesterolemia	Cohesion Phenomics Accession: SCV003836769.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

Arg744Arg in exon 15 of LDLR: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 31.3% (1377/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs5927).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Familial hypercholesterolemia mutations in Petrozavodsk: no similarity to St. Petersburg mutation spectrum.	Komarova TY	BMC medical genetics	2013	PMID: 24373485

Text-mined citations for rs5927 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 27, 2025

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.2232A>G (p.Arg744=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs5927 ...