ClinVar Miner

Submissions for variant NM_000093.4(COL5A1):c.3023C>T (p.Thr1008Met) (rs199735010)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199147 SCV000249906 uncertain significance not provided 2017-12-29 criteria provided, single submitter clinical testing The T1008M variant of uncertain significance in the COL5A1 gene has not been published as a pathogenic or benign variant to our knowledge. This variant has been identified in several individuals referred for Marfan/TAAD, and related disorders genetic testing at GeneDx; however, most individuals harbored additional cardiogenetic variants, and segregation data is limited for these individuals due to insufficient participation by informative family members. The T1008M variant was not observed with any significant frequency in either approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the Exome Aggregation Consortium. The T1008M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, while the T1008M variant is located in the triple helical region of the COL5A1 gene, it does not affect a Glycine residue in a Gly-X-Y motif within this region, which is where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
GenomeConnect, ClinGen RCV000509160 SCV000607028 not provided Ehlers-Danlos syndrome, classic type no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Illumina Clinical Services Laboratory,Illumina RCV000279787 SCV000478552 uncertain significance Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000509160 SCV000832763 uncertain significance Ehlers-Danlos syndrome, classic type 2018-04-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1008 of the COL5A1 protein (p.Thr1008Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs199735010, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 213047). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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