VCV000519611.20 - ClinVar

NM_000090.4(COL3A1):c.3793C>A (p.Leu1265Met)

Germline

Classification

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

Uncertain significance

5 out of 5 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.3793C>A (p.Leu1265Met)

Variation ID: 519611 Accession: VCV000519611.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q32.2 2: 189009191 (GRCh38) [ NCBI UCSC ] 2: 189873917 (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	Apr 14, 2018	Feb 25, 2025	Sep 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000090.4:c.3793C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000081.2:p.Leu1265Met	missense
NC_000002.12:g.189009191C>A
NC_000002.11:g.189873917C>A
NG_007404.1:g.39819C>A
LRG_3:g.39819C>A
LRG_3t1:c.3793C>A	LRG_3p1:p.Leu1265Met

... more HGVS ... less HGVS

Protein change

L1265M

Other names

Canonical SPDI

NC_000002.12:189009190:C: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) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA62563083 dbSNP: rs200052168 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 (1)	criteria provided, single submitter	Jun 20, 2024	RCV001591386.10
Ehlers-Danlos syndrome, type 4	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 23, 2024	RCV001346564.18
Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 18, 2023	RCV002314221.10

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 (Sep 16, 2021) 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: SCV000738542.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 29510914 Comment: The p.L1265M variant (also known as c.3793C>A), located in coding exon 48 of the COL3A1 gene, results from a C to A substitution at nucleotide … (more) The p.L1265M variant (also known as c.3793C>A), located in coding exon 48 of the COL3A1 gene, results from a C to A substitution at nucleotide position 3793. The leucine at codon 1265 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in a vascular genetic testing cohort (Hicks KL et al. J Vasc Surg, 2018 09;68:701-711). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jun 20, 2024) 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: SCV001814590.3 First in ClinVar: Sep 08, 2021 Last updated: Sep 29, 2024	Comment: Identified in a 41 year-old female with a ruptured Achilles tendon and no history of aortic or arterial disease in published literature; however, no segregation … (more) Identified in a 41 year-old female with a ruptured Achilles tendon and no history of aortic or arterial disease in published literature; however, no segregation or functional studies were reported (PMID: 29510914); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); This variant is associated with the following publications: (PMID: 29510914) (less)
Uncertain significance (Sep 27, 2023) 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: SCV001540781.5 First in ClinVar: Mar 22, 2021 Last updated: Feb 25, 2025	Publications: PubMed (1) PubMed: 29510914 Comment: This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1265 of the COL3A1 protein (p.Leu1265Met). … (more) This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1265 of the COL3A1 protein (p.Leu1265Met). This variant is present in population databases (rs200052168, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of COL3A1-related conditions (PMID: 29510914). ClinVar contains an entry for this variant (Variation ID: 519611). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 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 (Dec 18, 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: SCV004363044.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 29510914 Comment: This missense variant replaces leucine with methionine at codon 1265 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces leucine with methionine at codon 1265 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 been reported in an individual suspected of having genetically triggered vascular disease (PMID: 29510914). This variant has been identified in 3/250658 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)
Uncertain Significance (Sep 23, 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: SCV004827603.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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)	Publications: PubMed (1) PubMed: 29510914 Comment: This missense variant replaces leucine with methionine at codon 1265 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces leucine with methionine at codon 1265 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 been reported in an individual suspected of having genetically triggered vascular disease (PMID: 29510914). This variant has been identified in 3/250658 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: 6 Zygosity: Single Heterozygote

Comment:

The p.L1265M variant (also known as c.3793C>A), located in coding exon 48 of the COL3A1 gene, results from a C to A substitution at nucleotide position 3793. The leucine at codon 1265 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in a vascular genetic testing cohort (Hicks KL et al. J Vasc Surg, 2018 09;68:701-711). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Identified in a 41 year-old female with a ruptured Achilles tendon and no history of aortic or arterial disease in published literature; however, no segregation or functional studies were reported (PMID: 29510914); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); This variant is associated with the following publications: (PMID: 29510914)

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1265 of the COL3A1 protein (p.Leu1265Met). This variant is present in population databases (rs200052168, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of COL3A1-related conditions (PMID: 29510914). ClinVar contains an entry for this variant (Variation ID: 519611). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 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:

This missense variant replaces leucine with methionine at codon 1265 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 been reported in an individual suspected of having genetically triggered vascular disease (PMID: 29510914). This variant has been identified in 3/250658 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:

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
Testing patterns for genetically triggered aortic and arterial aneurysms and dissections at an academic center.	Hicks KL	Journal of vascular surgery	2018	PMID: 29510914

Text-mined citations for rs200052168 ...

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.3793C>A (p.Leu1265Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200052168 ...