VCV000426985.24 - ClinVar

NM_000090.4(COL3A1):c.1526G>A (p.Arg509His)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(1)

7 out of 8 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_000090.4(COL3A1):c.1526G>A (p.Arg509His)

Variation ID: 426985 Accession: VCV000426985.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q32.2 2: 188995708 (GRCh38) [ NCBI UCSC ] 2: 189860434 (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	May 22, 2017	Feb 25, 2025	Jan 8, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000090.4:c.1526G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000081.2:p.Arg509His	missense
NC_000002.12:g.188995708G>A
NC_000002.11:g.189860434G>A
NG_007404.1:g.26336G>A
LRG_3:g.26336G>A
LRG_3t1:c.1526G>A	LRG_3p1:p.Arg509His

... more HGVS ... less HGVS

Protein change

R509H

Other names

p.Arg509His

Canonical SPDI

NC_000002.12:188995707:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00004

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00007

Exome Aggregation Consortium (ExAC) 0.00010

Links

ClinGen: CA074449 dbSNP: rs568986390 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.
COL3A1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	3353	3487

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.
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Sep 26, 2024	RCV000489573.16
Ehlers-Danlos syndrome, type 4	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 8, 2025	RCV000818956.18
Familial thoracic aortic aneurysm and aortic dissection	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Mar 21, 2024	RCV001191863.16
Ehlers-Danlos syndrome, type 4 Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	not provided (1)	no classification provided	-	RCV002508936.9

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.	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 (Jul 22, 2021) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577583.6 First in ClinVar: May 22, 2017 Last updated: Mar 04, 2023	Comment: Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on … (more) Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (Stenson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 426985; Landrum et al., 2016) (less)
Uncertain significance (Feb 25, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002049791.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: The COL3A1 c.1526G>A; p.Arg509His variant (rs568986390), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 426985). This … (more) The COL3A1 c.1526G>A; p.Arg509His variant (rs568986390), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 426985). This variant is found in the general population with an overall allele frequency of 0.003% (6/164704 alleles) in the Genome Aggregation Database. The arginine at codon 509 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.693). However, given the lack of clinical and functional data, the significance of the p.Arg509His variant is uncertain at this time. (less)
Uncertain significance (Aug 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001359779.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Comment: This missense variant replaces arginine with histidine at codon 509 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces arginine with histidine at codon 509 of the COL3A1 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has been identified in 6/164704 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. (less)
Likely benign (Mar 21, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002709657.3 First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024	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 (Jan 08, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Ehlers-Danlos syndrome, type 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000959595.7 First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025	Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 509 of the COL3A1 protein (p.Arg509His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 509 of the COL3A1 protein (p.Arg509His). This variant is present in population databases (rs568986390, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 426985). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. 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 (Feb 05, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ehlers-Danlos syndrome, type 4 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004824603.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This missense variant replaces arginine with histidine at codon 509 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces arginine with histidine at codon 509 of the COL3A1 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/164704 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. (less) Number of individuals with the variant: 21 Zygosity: Single Heterozygote
Uncertain significance (Sep 26, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005408941.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Comment: BS1 Number of individuals with the variant: 1
not provided (-) N Not contributing to aggregate classification	no classification provided Method: phenotyping only	Ehlers-Danlos syndrome, type 4 Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002818379.2 First in ClinVar: Jan 07, 2023 Last updated: Jun 17, 2024	Comment: Variant classified as Uncertain significance and reported on 08-05-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more) Variant classified as Uncertain significance and reported on 08-05-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Myopia (present) , Depression (present) , Joint hypermobility (present) , Abnormal muscle physiology (present) Age: 40-49 years Sex: female Method: Gene Panel Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2021-08-05 Testing laboratory interpretation: Uncertain significance

Comment:

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (Stenson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 426985; Landrum et al., 2016)

Comment:

The COL3A1 c.1526G>A; p.Arg509His variant (rs568986390), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 426985). This variant is found in the general population with an overall allele frequency of 0.003% (6/164704 alleles) in the Genome Aggregation Database. The arginine at codon 509 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.693). However, given the lack of clinical and functional data, the significance of the p.Arg509His variant is uncertain at this time.

Comment:

This missense variant replaces arginine with histidine at codon 509 of the COL3A1 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has been identified in 6/164704 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.

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.

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 509 of the COL3A1 protein (p.Arg509His). This variant is present in population databases (rs568986390, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 426985). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. 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:

This missense variant replaces arginine with histidine at codon 509 of the COL3A1 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/164704 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.

Comment:

Variant classified as Uncertain significance and reported on 08-05-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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:

This missense variant replaces arginine with histidine at codon 509 of the COL3A1 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/164704 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.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs568986390 ...

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 Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_000090.4(COL3A1):c.1526G>A (p.Arg509His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs568986390 ...