ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.691-2A>G

dbSNP: rs1576463100
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000807317 SCV000947364 pathogenic Ehlers-Danlos syndrome, type 4 2019-10-13 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL3A1 are known to be pathogenic (PMID: 24922459). Experimental studies have shown that this change results in exon 9 skipping (PMID: 10923041). Exon 9 is also known as exon 10 in the literature. This variant has been observed in an individual affected with Ehlers-Danlos syndrome (PMID: 10923041). This variant is also known as c.793 -2A>G in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 8 of the COL3A1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000807317 SCV005399631 pathogenic Ehlers-Danlos syndrome, type 4 2023-12-21 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Dominant negative is due to missense variants affecting glycine residues in the Gly-X-Y repeat within the triple helical region, while loss of function is due to null variants (PMID: 29346445). (I) 0108 - This gene is associated with both recessive and dominant disease. There is no clear genotype-phenotype correlation between autosomal dominant Ehlers-Danlos syndrome, vascular type (MIM#130050) and autosomal recessive polymicrogyria with or without vascular-type EDS (MIM#618343). (I) 0112 - The condition associated with this gene has incomplete penetrance. This is associated with COL3A1 null variants (PMID: 20301667). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant inter- and intra-familial variability has been reported for the same pathogenic variants (PMID: 20301667). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). Skipping of the nearest exon was reported following RT-PCR analysis using sample from an individual with this variant (also known as c.793-2A>G, PMID: 10923041); however, the authors did not provide sequencing data to confirm the exon skipping. This abnormal splicing is expected to result in an inframe deletion, p.(Gly231_Pro248del), within the triple helical region (UniProt). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another splice site variant comparable to the one identified in this case has limited previous evidence for pathogenicity. c.691-1G>A has been reported as pathogenic by a clinical testing laboratory (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by a clinical testing laboratory (ClinVar). It has also been reported in an individual with vascular type Ehlers-Danlos syndrome, where c.793-2A>G has been used as alternative variant nomenclature (PMID: 10923041). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Cultured dermal fibroblasts from a heterozygous individual showed trypsin sensitive and abnormal thermal stability of collagen III (PMID: 10923041). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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