VCV001932273.4 - ClinVar

NM_000090.4(COL3A1):c.3580G>C (p.Gly1194Arg)

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.

(2)

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
Likely pathogenic(1); Uncertain significance(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.3580G>C (p.Gly1194Arg)

Variation ID: 1932273 Accession: VCV001932273.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q32.2 2: 189008978 (GRCh38) [ NCBI UCSC ] 2: 189873704 (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	Feb 7, 2023	Aug 18, 2024	Aug 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000090.4:c.3580G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000081.2:p.Gly1194Arg	missense
NC_000002.12:g.189008978G>C
NC_000002.11:g.189873704G>C
NG_007404.1:g.39606G>C
LRG_3:g.39606G>C
LRG_3t1:c.3580G>C	LRG_3p1:p.Gly1194Arg

... more HGVS ... less HGVS

Protein change

G1194R

Other names

Canonical SPDI

NC_000002.12:189008977:G:C

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.

Links

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	3041	3169

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 4	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 14, 2024	RCV002649397.4

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 (Feb 20, 2022)	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: SCV002969521.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Comment: 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 … (more) 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. 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 expected to disrupt COL3A1 protein function. This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1194 of the COL3A1 protein (p.Gly1194Arg). (less)
Likely pathogenic (Aug 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ehlers-Danlos syndrome, type 4 (Autosomal dominant inheritance) Affected status: yes Allele origin: paternal	Laboratorio de Genética Hospitales Universitarios Virgen de las Nieves y Clínico San Cecilio (Granada, Spain), Hospitales Universitarios Virgen de las Nieves y Clínico San Cecilio (Granada, Spain) Accession: SCV005187358.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024	Comment: This variant is located in a mutational hot spot in a critical and well-established protein functional domain. It has extremely low frequency in gnomAD population … (more) This variant is located in a mutational hot spot in a critical and well-established protein functional domain. It has extremely low frequency in gnomAD population databases. Computational prediction tools unanimously support a deleterious effect on the gene. In Clinvar was found like pathogenic variant with a different amino acid change at same codon (chr2:189873705:G>A) (PMID:25758994) (less) Indication for testing: HP:0006522 Repeated pneumothorax Age: 20-29 years Sex: male Ethnicity/Population group: Mediterranean Geographic origin: España Comment on evidence: Variant identified in a young man with repeated pneumothorax. He has familiar antecedents of aortic valve dilatation by paternal linage.

Comment:

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. 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 expected to disrupt COL3A1 protein function. This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1194 of the COL3A1 protein (p.Gly1194Arg).

Comment:

This variant is located in a mutational hot spot in a critical and well-established protein functional domain. It has extremely low frequency in gnomAD population databases. Computational prediction tools unanimously support a deleterious effect on the gene. In Clinvar was found like pathogenic variant with a different amino acid change at same codon (chr2:189873705:G>A) (PMID:25758994)

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

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 this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000090.4(COL3A1):c.3580G>C (p.Gly1194Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...