ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1149+5G>A

dbSNP: rs587779538
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000087478 SCV001505221 uncertain significance Ehlers-Danlos syndrome, type 4 2022-08-10 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 101241). This variant has been observed in individual(s) with clinical features of vascular Ehlers-Danlos syndrome (PMID: 24922459). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 16 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.
Ambry Genetics RCV002453420 SCV002615061 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2018-06-19 criteria provided, single submitter clinical testing The c.1149+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 16 in the COL3A1 gene. This alteration has been previously reported in a vascular Ehlers-Danlos syndrome (vEDS, also known as type IV) cohort, but clinical details were limited (Pepin MG et al. Genet. Med. 2014;16:881-8). RNA studies on cultured fibroblasts derived from a patient heterozygous for this variant have demonstrated that this alteration leads to exon skipping (personal communication, P. Byers). Two disease-causing mutations affecting the same donor splice site (c.1149+1G>A and c.1149+2T>G) also cause skipping of coding exon 16 (referred to as exon 17 in legacy nomenclature) (Chiodo AA et al. Biochem. J. 1995;311(Pt 3):939-43; Schwarze U et al. Am. J. Hum. Genet. 1997;61:1276-86). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Collagen Diagnostic Laboratory, University of Washington RCV000087478 SCV000120365 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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