Submissions for variant NM_000393.5(COL5A2):c.1579C>T (p.Arg527Cys)

gnomAD frequency: 0.00001  dbSNP: rs863223490

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199532	SCV000249958	uncertain significance	not provided	2024-01-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); At the mRNA level, in silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; At the protein level, in silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229469	SCV000755957	uncertain significance	Ehlers-Danlos syndrome, classic type, 1	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 527 of the COL5A2 protein (p.Arg527Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213097). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL5A2 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Mendelics	RCV002247621	SCV002518140	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399722	SCV002709496	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-02-14	criteria provided, single submitter	clinical testing	The p.R527C variant (also known as c.1579C>T), located in coding exon 24 of the COL5A2 gene, results from a C to T substitution at nucleotide position 1579. The arginine at codon 527 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002247621	SCV005204993	uncertain significance	not specified	2024-06-26	criteria provided, single submitter	clinical testing	Variant summary: COL5A2 c.1579C>T (p.Arg527Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250668 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1579C>T in individuals affected with Ehlers-Danlos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 213097). Based on the evidence outlined above, the variant was classified as uncertain significance.