VCV000199744.56 - ClinVar

NM_000090.4(COL3A1):c.3818A>G (p.Lys1273Arg)

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.

(10)

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(4); Benign(1); Likely benign(5)

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.3818A>G (p.Lys1273Arg)

Variation ID: 199744 Accession: VCV000199744.56

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q32.2 2: 189009216 (GRCh38) [ NCBI UCSC ] 2: 189873942 (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	Sep 16, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000090.4:c.3818A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000081.2:p.Lys1273Arg	missense
NC_000002.12:g.189009216A>G
NC_000002.11:g.189873942A>G
NG_007404.1:g.39844A>G
LRG_3:g.39844A>G
LRG_3t1:c.3818A>G	LRG_3p1:p.Lys1273Arg

... more HGVS ... less HGVS

Protein change

K1273R

Other names

p.K1273R:AAG>AGG

Canonical SPDI

NC_000002.12:189009215:A:G

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 (G)

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

Exome Aggregation Consortium (ExAC) 0.00008

The Genome Aggregation Database (gnomAD) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00013

Trans-Omics for Precision Medicine (TOPMed) 0.00015

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

Links

ClinGen: CA006720 dbSNP: rs144614075 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.
Ehlers-Danlos syndrome, type 3 Ehlers-Danlos syndrome, type 4	Uncertain significance (1)	criteria provided, single submitter	May 23, 2017	RCV000515270.10
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Dec 23, 2023	RCV000725829.24
Familial thoracic aortic aneurysm and aortic dissection	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Oct 1, 2021	RCV000771822.16
Ehlers-Danlos syndrome, type 4	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 30, 2024	RCV001087510.19

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 (May 23, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ehlers-Danlos syndrome, type 3 Ehlers-Danlos syndrome, type 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611385.1 First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017
Likely benign (Oct 08, 2019)	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: SCV000904527.2 First in ClinVar: May 20, 2019 Last updated: Jun 22, 2020
Likely benign (Jul 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001762374.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021	Publications: PubMed (3) PubMed: 26854089‚ 31075413‚ 31531849
Uncertain significance (Oct 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838691.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Likely benign (Jan 30, 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: SCV000262437.9 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024
Likely benign (Jul 17, 2020)	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: SCV000319224.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 25758994‚ 26854089‚ 28087566‚ 29590070‚ 30087447‚ 31531849 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 (Mar 03, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000339677.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL3A1 Number of individuals with the variant: 1 Sex: mixed
Benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ehlers-Danlos syndrome, type 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001299204.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 26854089‚ 25758994 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
Likely benign (Nov 09, 2021)	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: SCV002048320.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Uncertain significance (Dec 23, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000233388.15 First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024	Comment: Identified in individuals with arterial dissection and/or aneurysm in the published literature and classified as a variant of uncertain significance (PMID: 26854089, 25758994, 20825986); Identified … (more) Identified in individuals with arterial dissection and/or aneurysm in the published literature and classified as a variant of uncertain significance (PMID: 26854089, 25758994, 20825986); Identified in a proband with spontaneous iliac artery dissection in the published literature, but the variant did not segregate with disease in this family; a second cardiogenetic variant in the COL1A1 gene was identified in the proband that segregated with disease and was classified by the authors as pathogenic (PMID: 31531849); Identified in a patient with Marfan syndrome who also harbored a likely pathogenic variant in the FBN1 gene (PMID: 30087447); Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(K1106R); This variant is associated with the following publications: (PMID: 29590070, 25758994, 20825986, 31531849, 26854089, 30087447) (less)

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 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Comment:

Identified in individuals with arterial dissection and/or aneurysm in the published literature and classified as a variant of uncertain significance (PMID: 26854089, 25758994, 20825986); Identified in a proband with spontaneous iliac artery dissection in the published literature, but the variant did not segregate with disease in this family; a second cardiogenetic variant in the COL1A1 gene was identified in the proband that segregated with disease and was classified by the authors as pathogenic (PMID: 31531849); Identified in a patient with Marfan syndrome who also harbored a likely pathogenic variant in the FBN1 gene (PMID: 30087447); Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(K1106R); This variant is associated with the following publications: (PMID: 29590070, 25758994, 20825986, 31531849, 26854089, 30087447)

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
Classical Ehlers-Danlos syndrome with a propensity to arterial events: A new report on a French family with a COL1A1 p.(Arg312Cys) variant.	Adham S	Clinical genetics	2020	PMID: 31531849
Type III collagen (COL3A1): Gene and protein structure, tissue distribution, and associated diseases.	Kuivaniemi H	Gene	2019	PMID: 31075413
Association of modifiers and other genetic factors explain Marfan syndrome clinical variability.	Aubart M	European journal of human genetics : EJHG	2018	PMID: 30087447
Phenotype risk scores identify patients with unrecognized Mendelian disease patterns.	Bastarache L	Science (New York, N.Y.)	2018	PMID: 29590070
Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults.	Seidelmann SB	Circulation. Cardiovascular genetics	2017	PMID: 28087566
Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing.	Schubert JA	American journal of medical genetics. Part A	2016	PMID: 26854089
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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL3A1	-	-	-	-

Text-mined citations for rs144614075 ...

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.3818A>G (p.Lys1273Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144614075 ...