ClinVar Miner

Submissions for variant NM_000093.4(COL5A1):c.3184C>T (p.Arg1062Ter) (rs387906606)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199830 SCV000249812 pathogenic not provided 2017-03-27 criteria provided, single submitter clinical testing The R1062X pathogenic variant in the COL5A1 gene has been previously reported in association with classical Ehlers-Danlos syndrome (cEDS, EDS type I and II) (Malfait et al., 2005; Borck et al. 2010; Symoens et al., 2012). Malfait et al. (2005) reported this variant in a four-year-old female diagnosed with cEDS due to her history of smooth hyperextensible skin, atrophic scars and joint hypermobility. In this proband, R1062X was found in cis (on the same allele) with the G530S benign variant, and parental testing showed that G530S was paternally inherited but R1062X was absent in the father, suggesting R1062X occurred de novo in this child. Borck et al. (2010) reported R1062X in a 42-year-old German male who presented with a rupture of the left common iliac artery and was diagnosed with cEDS due to his history of skin hyperextensibility, atrophic scars, easy bruising, inguinal hernias, and molluscoid pseudotumors. Parental testing, with identity studies, confirmed R1062X occurred de novo in this patient and segregated with disease in his two affected children (Borck et al., 2010). The R1062X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Expression studies of the COL5A1 gene using complementary DNA (cDNA) from a patient heterozygous for the R1062X variant demonstrated significantly reduced expression of one COL5A1 allele, suggesting the presence of R1062X results in a nonfunctional (null) COL5A1 allele due to nonsense-mediated decay (Malfait et al., 2005; Symoens et al., 2012). Furthermore, multiple other nonsense variants in the COL5A1 gene have been reported in Human Gene Mutation Database in association with cEDS (Stenson et al., 2014). Finally, the R1062X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
OMIM RCV000022486 SCV000043775 pathogenic Ehlers-Danlos syndrome, classic type 2010-08-01 no assertion criteria provided literature only

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