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NM_000090.4(COL3A1):c.4254+3A>G AND Ehlers-Danlos syndrome, type 4

Germline classification:
Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:
Nov 17, 2024
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000794942.13

Allele description [Variation Report for NM_000090.4(COL3A1):c.4254+3A>G]

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

Gene:
COL3A1:collagen type III alpha 1 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q32.2
Genomic location:
Preferred name:
NM_000090.4(COL3A1):c.4254+3A>G
HGVS:
  • NC_000002.12:g.189010893A>G
  • NG_007404.1:g.41521A>G
  • NM_000090.4:c.4254+3A>GMANE SELECT
  • LRG_3t1:c.4254+3A>G
  • LRG_3:g.41521A>G
  • NC_000002.11:g.189875619A>G
  • NM_000090.3:c.4254+3A>G
Links:
dbSNP: rs376799861
NCBI 1000 Genomes Browser:
rs376799861
Molecular consequence:
  • NM_000090.4:c.4254+3A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Ehlers-Danlos syndrome, type 4
Synonyms:
Ehlers-Danlos syndrome vascular type; Ehlers Danlos syndrome, ecchymotic type; Ehlers Danlos syndrome, arterial type; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0017314; MedGen: C0268338; Orphanet: 286; OMIM: 130050

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000934379Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Nov 17, 2024) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001190436Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Aug 13, 2019) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]
PMID:
9536098
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000934379.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV001190436.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 25, 2025