VCV000161272.45 - ClinVar

NM_000527.5(LDLR):c.58G>A (p.Gly20Arg)

Germline

Top reviewed classifications are shown here.

Submission summary:

24 submissions

24 submitters

7 conditions

Reviewed by expert panel

Benign

Jun 2021 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.58G>A (p.Gly20Arg)

Variation ID: 161272 Accession: VCV000161272.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11089606 (GRCh38) [ NCBI UCSC ] 19: 11200282 (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	Dec 7, 2014	Oct 20, 2024	Jun 7, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.58G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Gly20Arg	missense
NM_001195798.2:c.58G>A	NP_001182727.1:p.Gly20Arg	missense
NM_001195799.2:c.58G>A	NP_001182728.1:p.Gly20Arg	missense
NM_001195800.2:c.58G>A	NP_001182729.1:p.Gly20Arg	missense
NM_001195803.2:c.58G>A	NP_001182732.1:p.Gly20Arg	missense
NR_163945.1:n.54C>T		non-coding transcript variant
NC_000019.10:g.11089606G>A
NC_000019.9:g.11200282G>A
NG_009060.1:g.5226G>A
LRG_274:g.5226G>A
LRG_274t1:c.58G>A	LRG_274p1:p.Gly20Arg

... more HGVS ... less HGVS

Protein change

G20R

Other names

NM_000527.5(LDLR):c.58G>A

Canonical SPDI

NC_000019.10:11089605:G:A

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

no known functional consequence

non-disruptive missense [submitted by Dept. of Genetics and Pharmacogenomics, Merck Research Labs]

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.

0.00060 (A)

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

1000 Genomes Project 30x 0.00047

Trans-Omics for Precision Medicine (TOPMed) 0.00052

The Genome Aggregation Database (gnomAD) 0.00053

1000 Genomes Project 0.00060

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069

The Genome Aggregation Database (gnomAD), exomes 0.00074

Exome Aggregation Consortium (ExAC) 0.00105

Links

ClinGen: CA023728 LDLR-LOVD, British Heart Foundation: LDLR_000013 dbSNP: rs147509697 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	Benign (10)	reviewed by expert panel	Jun 7, 2021	RCV000211611.31
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000161949.26
not specified	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Aug 31, 2020	RCV000609054.12
Familial hypercholesterolemia	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000771169.18
Hypercholesterolemia	Uncertain significance (1)	criteria provided, single submitter	Jun 1, 2014	RCV002051665.10
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	May 22, 2018	RCV002354338.9
LDLR-related disorder	Likely benign (1)	no assertion criteria provided	Jun 2, 2024	RCV003952707.2

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.
Benign (Jun 07, 2021)	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1) Method: curation	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel FDA Recognized Database Accession: SCV001960907.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/be4b2a4c-4d4f-4372-99c1-a538940653d5 Comment: The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) as defined by the ClinGen … (more) The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database. BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met. BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy. Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. (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: SCV000294427.2 First in ClinVar: Jul 29, 2016 Last updated: May 26, 2018	Publications: PubMed (10) PubMed: 12436241‚ 15556094‚ 15823276‚ 16250003‚ 17347910‚ 19318025‚ 20145306‚ 21310417‚ 23375686‚ 24373485 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1 Observation 3: Number of individuals with the variant: 1 Observation 4: Number of individuals with the variant: 1 Observation 5: Number of individuals with the variant: 1 Observation 6: Number of individuals with the variant: 1 Observation 7: Number of individuals with the variant: 1 Observation 8: Number of individuals with the variant: 1 Observation 9: Number of individuals with the variant: 1 Observation 10: Number of individuals with the variant: 1
Uncertain significance (Feb 19, 2016)	criteria provided, single submitter (Mayo Cardiovascular Biomarkers Research Laboratory LDLR variant interpretation criteria, 2015) Method: research	Hypercholesterolemia, familial, 1 2 cases with mild hypercholesterolemia Affected status: no Allele origin: germline	Cardiovascular Biomarker Research Laboratory, Mayo Clinic Study: RIGHT Accession: SCV000266321.2 First in ClinVar: Mar 24, 2016 Last updated: Apr 16, 2017	Publications: PubMed (1) PubMed: 28145427 Comment: MAF =<0.3%. "Little/No effect" on the LDL receptor activity based on experimental validation. Indication for testing: Familial hypercholesterolemia Age: 55-66 years Sex: male Ethnicity/Population group: White Geographic origin: United States
Likely benign (May 12, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemias Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000903098.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Feb 12, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV001433283.1 First in ClinVar: Sep 24, 2020 Last updated: Sep 24, 2020
Benign (May 24, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002047182.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022	Publications: PubMed (4) PubMed: 24373485‚ 26361156‚ 27175606‚ 25781017
Benign (Apr 07, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004562294.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024
Benign (Dec 11, 2023)	criteria provided, single submitter (Chora et al. (Genet Med. 2022)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	GENinCode PLC Accession: SCV005074000.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024
Benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004011015.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: LDLR: BS3:Supporting, BS1, BS2 Number of individuals with the variant: 3
Uncertain significance (Jun 01, 2014)	criteria provided, single submitter (Amendola et al. (Genome Res. 2015)) Method: research	Hypercholesterolaemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190291.2 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript	Publications: PubMed (1) PubMed: 25637381 Comment: Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Uncertain significance (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000322872.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Comment: 0/190 non-FH alleles; 0/150 normolipidemic chromosomes Observation 1: Comment on evidence: %MAF (ExAC):0.1046 Observation 2: Comment on evidence: Heterologous cells (CHO), FACS assays Result: Normal cell surface LDLR, binding and uptake
Benign (Nov 05, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation Additional submitter: Centre of Molecular Biology and Gene Therapy, University Hospital Brno Accession: SCV000540713.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Publications: PubMed (2) PubMed: 27175606‚ 22698793 Comment: A functional analysis was previously published (PavlouÅ¡kovÃ¡ et al, 2016). This variant has no effect on LDLR protein function. Number of individuals with the variant: 27 Clinical Features: Hypercholesterolemia (present) , Ischemic stroke (present) Family history: yes Age: 14-74 years Sex: mixed Ethnicity/Population group: Caucasian Geographic origin: Czech Republic Tissue: Whole blood
Uncertain significance (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Fundacion Hipercolesterolemia Familiar Study: SAFEHEART Accession: SCV000607408.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017	Observation 1: Comment on evidence: %MAF(ExAC):0.1046 Observation 2: Comment on evidence: Heterologous cells (CHO), FACS assays Result: Normal cell surface LDLR, LDL-LDLR binding and uptake
Likely benign (Apr 05, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000730501.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	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 … (more) 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)
Uncertain significance (Aug 16, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001288138.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (11) PubMed: 23130880‚ 15556094‚ 16250003‚ 15823276‚ 12436241‚ 24373485‚ 22698793‚ 20145306‚ 21935675‚ 22883975‚ 17347910 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Aug 31, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697241.2 First in ClinVar: Feb 28, 2015 Last updated: Sep 14, 2020	Publications: PubMed (22) PubMed: 15823276‚ 12436241‚ 17347910‚ 16250003‚ 20145306‚ 21935675‚ 23375686‚ 22698793‚ 24055113‚ 22923420‚ 25637381‚ 24627126‚ 26361156‚ 24507775‚ 25487149‚ 27824480‚ 24373485‚ 26020417‚ 27175606‚ 23130880‚ 26415676‚ 25647241 Comment: Variant summary: LDLR c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: LDLR c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 255636 control chromosomes, predominantly at a frequency of 0.0024 within the Ashkenazi Jewish subpopulation in the gnomAD database. This frequency is approximately 2-fold the estimated maximum allele frequency expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.58G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia, however without evidence for co-segrgation with disease. In a family with Familial Hypercholesterolemia (FH), 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Medeiros_2014). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants in LDLR have also been reported in FH patients in the literature (examples- Tejedor_2011, Komarova_2013, Klancar_2015), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, showing no damaging effects by this variant (examples- Thormaehlen_2015, Pavlouskova_2016). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=5; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Benign (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440726.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Likely benign (Feb 01, 2024)	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: SCV000556775.9 First in ClinVar: Apr 16, 2017 Last updated: Feb 28, 2024
Likely benign (May 22, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002653247.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (20) PubMed: 12436241‚ 15556094‚ 15823276‚ 16250003‚ 17347910‚ 20145306‚ 21310417‚ 21935675‚ 22698793‚ 22883975‚ 23375686‚ 24055113‚ 24373485‚ 25487149‚ 25637381‚ 25647241‚ 26342331‚ 26415676‚ 27175606‚ 27784735 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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)
Uncertain significance (Nov 29, 2010)	no assertion criteria provided Method: clinical testing	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital Accession: SCV000268533.1 First in ClinVar: May 21, 2016 Last updated: May 21, 2016	Number of individuals with the variant: 2
Likely benign (Jun 02, 2024)	no assertion criteria provided Method: clinical testing	LDLR-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004773397.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Pathogenic (-)	no assertion criteria provided Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000605999.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017
Likely benign (Jan 08, 2020)	no assertion criteria provided Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001463950.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
not provided (-)	no classification provided (in vitro) Method: in vitro	not provided Affected status: not applicable Allele origin: not applicable	Dept. of Genetics and Pharmacogenomics, Merck Research Labs Accession: SCV000189524.1 First in ClinVar: Feb 28, 2015 Last updated: Feb 28, 2015 Comment: In vitro functional profiling of LDL-receptor missense alleles identified through large-scale association testing	Publications: PubMed (1) PubMed: 25647241
click to load more click to collapse

Comment:

The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database. BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met. BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy. Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign.

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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Variant summary: LDLR c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 255636 control chromosomes, predominantly at a frequency of 0.0024 within the Ashkenazi Jewish subpopulation in the gnomAD database. This frequency is approximately 2-fold the estimated maximum allele frequency expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.58G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia, however without evidence for co-segrgation with disease. In a family with Familial Hypercholesterolemia (FH), 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Medeiros_2014). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants in LDLR have also been reported in FH patients in the literature (examples- Tejedor_2011, Komarova_2013, Klancar_2015), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, showing no damaging effects by this variant (examples- Thormaehlen_2015, Pavlouskova_2016). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=5; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as likely benign.

Comment:

This alteration is classified as likely 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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
no known functional consequence	Method not provided	Result not provided	Dept. of Genetics and Pharmacogenomics, Merck Research Labs Accession: SCV000189524.1	Publications PubMed (1) Comment: non-disruptive missense

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals.	Safarova MS	European journal of human genetics : EJHG	2017	PMID: 28145427
The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey.	Gabčová D	Physiological research	2017	PMID: 27824480
Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship.	Sánchez-Hernández RM	Circulation. Cardiovascular genetics	2016	PMID: 27784735
Functional analysis of the p.(Leu15Pro) and p.(Gly20Arg) sequence changes in the signal sequence of LDL receptor.	Pavloušková J	Atherosclerosis	2016	PMID: 27175606
Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement.	Medeiros AM	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26020417
Next-generation-sequencing-based identification of familial hypercholesterolemia-related mutations in subjects with increased LDL-C levels in a latvian population.	Radovica-Spalvina I	BMC medical genetics	2015	PMID: 26415676
Universal Screening for Familial Hypercholesterolemia in Children.	Klančar G	Journal of the American College of Cardiology	2015	PMID: 26361156
Contribution of mutations in low density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) genes to familial combined hyperlipidemia (FCHL): a reappraisal by using a resequencing approach.	Minicocci I	Atherosclerosis	2015	PMID: 26342331
Correction: systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.	PLOS Genetics Staff	PLoS genetics	2015	PMID: 25781017
Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.	Thormaehlen AS	PLoS genetics	2015	PMID: 25647241
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.	Do R	Nature	2015	PMID: 25487149
Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia.	Medeiros AM	Journal of lipid research	2014	PMID: 24627126
Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.	Lange LA	American journal of human genetics	2014	PMID: 24507775
Familial hypercholesterolemia mutations in Petrozavodsk: no similarity to St. Petersburg mutation spectrum.	Komarova TY	BMC medical genetics	2013	PMID: 24373485
Actionable, pathogenic incidental findings in 1,000 participants' exomes.	Dorschner MO	American journal of human genetics	2013	PMID: 24055113
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.	Bertolini S	Atherosclerosis	2013	PMID: 23375686
Mutation detection in Croatian patients with familial hypercholesterolemia.	Pećin I	Annals of human genetics	2013	PMID: 23130880
Pooled DNA resequencing of 68 myocardial infarction candidate genes in French canadians.	Beaudoin M	Circulation. Cardiovascular genetics	2012	PMID: 22923420
Genetic analysis of familial hypercholesterolaemia in Western Australia.	Hooper AJ	Atherosclerosis	2012	PMID: 22883975
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.	Tichý L	Atherosclerosis	2012	PMID: 22698793
New contributions to the study of common double mutants in the human LDL receptor gene.	Tejedor MT	Die Naturwissenschaften	2011	PMID: 21935675
An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia.	Dušková L	Atherosclerosis	2011	PMID: 21310417
Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.	Chmara M	Journal of applied genetics	2010	PMID: 20145306
Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.	Alonso R	Clinical biochemistry	2009	PMID: 19318025
Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations.	Widhalm K	Journal of inherited metabolic disease	2007	PMID: 17347910
Update of the molecular basis of familial hypercholesterolemia in The Netherlands.	Fouchier SW	Human mutation	2005	PMID: 16250003
The molecular basis of familial hypercholesterolaemia in Turkish patients.	Sözen MM	Atherosclerosis	2005	PMID: 15823276
Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective.	Laurie AD	Atherosclerosis. Supplements	2004	PMID: 15556094
Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia.	Amsellem S	Human genetics	2002	PMID: 12436241
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/be4b2a4c-4d4f-4372-99c1-a538940653d5	-	-	-	-
click to load more click to collapse

Text-mined citations for rs147509697 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.58G>A (p.Gly20Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs147509697 ...