Submissions for variant NM_000093.5(COL5A1):c.2285C>T (p.Pro762Leu)

gnomAD frequency: 0.00004  dbSNP: rs138259992

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195484	SCV000249804	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing	Identified in a patient with a hereditary connective tissue disorder (HCTD) and carotid artery aneurysm and dissection (CAAD) in published literature (PMID: 30675029); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (PMID: 22696272; HGMD); This variant is associated with the following publications: (PMID: 22696272, 30675029, 33189937)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229451	SCV000631465	uncertain significance	Ehlers-Danlos syndrome, classic type, 1	2024-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 762 of the COL5A1 protein (p.Pro762Leu). This variant is present in population databases (rs138259992, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COL5A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 212948). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277475	SCV002565691	uncertain significance	Ehlers-Danlos syndrome	2019-04-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000195484	SCV004225170	uncertain significance	not provided	2022-11-17	criteria provided, single submitter	clinical testing	BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237687	SCV005885413	likely benign	not specified	2025-02-21	criteria provided, single submitter	clinical testing	Variant summary: COL5A1 c.2285C>T (p.Pro762Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 251374 control chromosomes. The observed variant frequency is approximately 1.27 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A1 causing Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, classic type, 1 phenotype (3.1e-05). c.2285C>T has been reported in the literature in a heterozygous individual affected with Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, classic type, 1 (Renner_2019); however, this individual carries a variant in another gene. These report(s) do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, classic type, 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30675029). ClinVar contains an entry for this variant (Variation ID: 212948). Based on the evidence outlined above, the variant was classified as likely benign.