ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.4254G>A (p.Thr1418=) (rs587779565)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Collagen Diagnostic Laboratory,University of Washington RCV000087514 SCV000120401 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing
GeneDx RCV000522589 SCV000617610 pathogenic not provided 2018-04-12 criteria provided, single submitter clinical testing A pathogenic variant was identified in the COL3A1 gene. The c.4254 G>A variant was reported in three individuals from two families with vEDS (Rigelsky et al., 2011; Pepin et al., 2014). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.4254 G>A variant results in a single nucleotide substitution in the last position of exon 51, which is the penultimate exon of the COL3A1 gene. In silico analysis predicts this substitution to destroy the natural splice donor site of intron 51. Functional studies of fibroblasts from a patient with this variant demonstrated use of an upstream cryptic splice donor site that led to a translational frameshift. The aberrant mRNA transcript was observed to be stable but the truncated protein product was not incorporated into the trimer procollagen molecule, which resulted in functional haploinsufficiency with production of half the normal amount of type III procollagen (Rigelsky et al., 2011). Haploinsufficiency of COL3A1 is an established mechanism in vEDS and multiple splicing variants and downstream loss of function variants have been reported in HGMD in association with vEDS (Stenson et al., 2014).

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