VCV000372575.26 - ClinVar

NM_000090.4(COL3A1):c.4254+3A>G

Germline

Classification

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

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

7 out of 7 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.4254+3A>G

Variation ID: 372575 Accession: VCV000372575.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q32.2 2: 189010893 (GRCh38) [ NCBI UCSC ] 2: 189875619 (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	Jan 9, 2017	Feb 25, 2025	Dec 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000090.4:c.4254+3A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NC_000002.12:g.189010893A>G
NC_000002.11:g.189875619A>G
NG_007404.1:g.41521A>G
LRG_3:g.41521A>G
LRG_3t1:c.4254+3A>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:189010892: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) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA076519 dbSNP: rs376799861 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 (2)	criteria provided, multiple submitters, no conflicts	Jun 17, 2021	RCV000414364.7
Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 10, 2024	RCV001187661.8
Ehlers-Danlos syndrome, type 4	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Nov 17, 2024	RCV000794942.13
Ehlers-Danlos syndrome, type 4 Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	Uncertain significance (1)	criteria provided, single submitter	Mar 30, 2021	RCV003224269.2

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 (Dec 12, 2016) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000490918.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Comment: The c.4254+3A>G variant in the COL3A1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This … (more) The c.4254+3A>G variant in the COL3A1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to damage or destroy the splice donor site in intron 50, and may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. The c.4254+3A>G variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.4254+3A>G as a variant of uncertain significance. (less)
Uncertain significance (Aug 13, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ehlers-Danlos syndrome, type 4 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV001190436.1 First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020	Comment: COL3A1 NM_000090.3 exon 50 c.4254+3A>G: This variant has not been reported in the literature but is present in 0.005% (2/34588) of Latino alleles in the … (more) COL3A1 NM_000090.3 exon 50 c.4254+3A>G: This variant has not been reported in the literature but is present in 0.005% (2/34588) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-189875619-A-G). This variant is present in ClinVar (Variation ID:372575). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence, but splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Uncertain significance (Jun 17, 2021) 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: SCV001714072.2 First in ClinVar: Jun 15, 2021 Last updated: Sep 20, 2023
Uncertain significance (Jun 29, 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: SCV001354520.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Comment: This variant causes an A to G nucleotide substitution at the +3 position of intron 50 of the COL3A1 gene. Splice prediction tools are inconclusive … (more) This variant causes an A to G nucleotide substitution at the +3 position of intron 50 of the COL3A1 gene. Splice prediction tools are inconclusive regarding the impact of this variant on RNA splicing. 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 6/251146 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 pathogenic (Nov 17, 2024) 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: SCV000934379.7 First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025	Publications: PubMed (2) PubMed: 17576681‚ 9536098 Comment: This sequence change falls in intron 50 of the COL3A1 gene. It does not directly change the encoded amino acid sequence of the COL3A1 protein. … (more) This sequence change falls in intron 50 of the COL3A1 gene. It does not directly change the encoded amino acid sequence of the COL3A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs376799861, gnomAD 0.006%). This variant has been observed in individuals with clinical features of COL3A1-related conditions (internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372575). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Uncertain significance (Mar 30, 2021) C Contributing to aggregate classification	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: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003919824.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: COL3A1 NM_000090.3 exon 50 c.4254+3A>G: This variant has not been reported in the literature but is present in 0.005% (2/34588) of Latino alleles in the … (more) COL3A1 NM_000090.3 exon 50 c.4254+3A>G: This variant has not been reported in the literature but is present in 0.005% (2/34588) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-189875619-A-G). This variant is present in ClinVar (Variation ID:372575). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence, but splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Uncertain significance (Dec 10, 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: SCV002627019.3 First in ClinVar: Nov 29, 2022 Last updated: Jan 13, 2025	Comment: The c.4254+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 50 in the COL3A1 gene. This variant was identified … (more) The c.4254+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 50 in the COL3A1 gene. This variant was identified in one or more individuals with features consistent with vascular Ehlers-Danlos syndrome (EDS) and segregated with disease in at least one family (external communication). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. (less)

Comment:

The c.4254+3A>G variant in the COL3A1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to damage or destroy the splice donor site in intron 50, and may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. The c.4254+3A>G variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.4254+3A>G as a variant of uncertain significance.

Comment:

COL3A1 NM_000090.3 exon 50 c.4254+3A>G: This variant has not been reported in the literature but is present in 0.005% (2/34588) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-189875619-A-G). This variant is present in ClinVar (Variation ID:372575). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence, but splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Comment:

This variant causes an A to G nucleotide substitution at the +3 position of intron 50 of the COL3A1 gene. Splice prediction tools are inconclusive regarding the impact of this variant on RNA splicing. 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 6/251146 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 sequence change falls in intron 50 of the COL3A1 gene. It does not directly change the encoded amino acid sequence of the COL3A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs376799861, gnomAD 0.006%). This variant has been observed in individuals with clinical features of COL3A1-related conditions (internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372575). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

The c.4254+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 50 in the COL3A1 gene. This variant was identified in one or more individuals with features consistent with vascular Ehlers-Danlos syndrome (EDS) and segregated with disease in at least one family (external communication). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs376799861 ...

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.4254+3A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs376799861 ...