VCV000199718.26 - ClinVar

NM_000090.4(COL3A1):c.1165A>T (p.Asn389Tyr)

Germline

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.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(6); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000090.4(COL3A1):c.1165A>T (p.Asn389Tyr)

Variation ID: 199718 Accession: VCV000199718.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q32.2 2: 188994053 (GRCh38) [ NCBI UCSC ] 2: 189858779 (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	Oct 8, 2024	Jul 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000090.4:c.1165A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000081.2:p.Asn389Tyr	missense
NC_000002.12:g.188994053A>T
NC_000002.11:g.189858779A>T
NG_007404.1:g.24681A>T
LRG_3:g.24681A>T
LRG_3t1:c.1165A>T	LRG_3p1:p.Asn389Tyr

... more HGVS ... less HGVS

Protein change

N389Y

Other names

p.N389Y:AAT>TAT

Canonical SPDI

NC_000002.12:188994052:A:T

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.

0.00020 (T)

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

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00006

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00010

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA004110 dbSNP: rs200394946 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	3056	3185

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 (2)	criteria provided, multiple submitters, no conflicts	Jul 9, 2024	RCV000181079.17
Ehlers-Danlos syndrome, type 4	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 27, 2024	RCV000465133.17
Familial thoracic aortic aneurysm and aortic dissection	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Dec 20, 2022	RCV000778019.15
Ehlers-Danlos syndrome, type 4 Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	Uncertain significance (1)	criteria provided, single submitter	Aug 20, 2021	RCV002478603.8
COL3A1-related disorder	Uncertain significance (1)	no assertion criteria provided	Jan 22, 2024	RCV004537521.2

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.
Uncertain significance (Aug 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ehlers-Danlos syndrome, type 4 Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000896914.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Jun 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003828137.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jan 27, 2024)	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: SCV000541785.6 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 28492532‚ 25758994‚ 31719132 Comment: This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 389 of the COL3A1 protein (p.Asn389Tyr). … (more) This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 389 of the COL3A1 protein (p.Asn389Tyr). This variant is present in population databases (rs200394946, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome or stroke (PMID: 25758994, 31719132). ClinVar contains an entry for this variant (Variation ID: 199718). 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 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 (Dec 20, 2022)	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: SCV000914129.4 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 25758994 Comment: This missense variant replaces asparagine with tyrosine at codon 389 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces asparagine with tyrosine at codon 389 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with possible vascular Ehlers-Danlos syndrome (PMID: 25758994). This variant has been identified in 28/282770 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)
Benign (Sep 07, 2022)	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: SCV000320669.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	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 … (more) 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)
Uncertain Significance (Dec 13, 2023)	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: SCV004826885.1 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)	Publications: PubMed (1) PubMed: 25758994 Comment: This missense variant replaces asparagine with tyrosine at codon 389 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces asparagine with tyrosine at codon 389 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with possible vascular Ehlers-Danlos syndrome (PMID: 25758994). This variant has been identified in 28/282770 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: 23
Uncertain significance (Jul 09, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000233355.14 First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024	Comment: Reported in a female with internal carotid dissection and skin hyperelasticity, whose mother with carotid artery dissection also harbored the same variant (PMID: 25758994); Reported … (more) Reported in a female with internal carotid dissection and skin hyperelasticity, whose mother with carotid artery dissection also harbored the same variant (PMID: 25758994); Reported in an individual with younger-onset small vessel disease (PMID: 31719132); 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 (HGMD); This variant is associated with the following publications: (PMID: 34318601, 33974636, 25758994, 31719132) (less)
Uncertain significance (Jan 22, 2024)	no assertion criteria provided Method: clinical testing	COL3A1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004108469.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The COL3A1 c.1165A>T variant is predicted to result in the amino acid substitution p.Asn389Tyr. This variant has been reported in an individual with possible classical … (more) The COL3A1 c.1165A>T variant is predicted to result in the amino acid substitution p.Asn389Tyr. This variant has been reported in an individual with possible classical Ehlers-Danlos syndrome (Supplementary results 2, Group 3 and Supplementary Table 4c, Frank et al 2015. PubMed ID: 25758994). This variant was also reported in a study analyzing the frequency of variants identified in small vessel disease (SVD) associated genes in individuals with younger-onset apparently sporadic SVD stroke (Tan et al. 2019. PubMed ID: 31719132) and in a study of individuals with Chiari malformation type 1 (Reported as rs200394946, Table S5, Urbizu et al. 2021. PubMed ID: 33974636). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 389 of the COL3A1 protein (p.Asn389Tyr). This variant is present in population databases (rs200394946, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome or stroke (PMID: 25758994, 31719132). ClinVar contains an entry for this variant (Variation ID: 199718). 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 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 asparagine with tyrosine at codon 389 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with possible vascular Ehlers-Danlos syndrome (PMID: 25758994). This variant has been identified in 28/282770 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 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:

Reported in a female with internal carotid dissection and skin hyperelasticity, whose mother with carotid artery dissection also harbored the same variant (PMID: 25758994); Reported in an individual with younger-onset small vessel disease (PMID: 31719132); 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 (HGMD); This variant is associated with the following publications: (PMID: 34318601, 33974636, 25758994, 31719132)

Comment:

The COL3A1 c.1165A>T variant is predicted to result in the amino acid substitution p.Asn389Tyr. This variant has been reported in an individual with possible classical Ehlers-Danlos syndrome (Supplementary results 2, Group 3 and Supplementary Table 4c, Frank et al 2015. PubMed ID: 25758994). This variant was also reported in a study analyzing the frequency of variants identified in small vessel disease (SVD) associated genes in individuals with younger-onset apparently sporadic SVD stroke (Tan et al. 2019. PubMed ID: 31719132) and in a study of individuals with Chiari malformation type 1 (Reported as rs200394946, Table S5, Urbizu et al. 2021. PubMed ID: 33974636). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
How common are single gene mutations as a cause for lacunar stroke? A targeted gene panel study.	Tan RYY	Neurology	2019	PMID: 31719132
The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome.	Frank M	European journal of human genetics : EJHG	2015	PMID: 25758994

Text-mined citations for rs200394946 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000090.4(COL3A1):c.1165A>T (p.Asn389Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200394946 ...