Submissions for variant NM_000093.5(COL5A1):c.4121C>T (p.Thr1374Met)

gnomAD frequency: 0.00014  dbSNP: rs151115748

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000762590	SCV000567471	uncertain significance	not provided	2022-06-09	criteria provided, single submitter	clinical testing	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); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22696272)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002231099	SCV000631514	uncertain significance	Ehlers-Danlos syndrome, classic type, 1	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1374 of the COL5A1 protein (p.Thr1374Met). This variant is present in population databases (rs151115748, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. 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: 419573). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Ambry Genetics	RCV002313245	SCV000738619	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-02-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000762590	SCV000892923	likely benign	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279240	SCV002565740	uncertain significance	Ehlers-Danlos syndrome	2020-07-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002231099	SCV002581683	uncertain significance	Ehlers-Danlos syndrome, classic type, 1	2021-08-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003942586	SCV004769192	likely benign	COL5A1-related disorder	2023-10-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689755	SCV005184780	likely benign	not specified	2024-05-13	criteria provided, single submitter	clinical testing	Variant summary: COL5A1 c.4121C>T (p.Thr1374Met) 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. In addition, this variant disrupts the penultimate nucleotide of exon 52, and therefore can affect splicing. 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 0.00023 in 251418 control chromosomes. The observed variant frequency is approximately 7.25 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A1 causing Ehlers-Danlos Syndrome phenotype (3.1e-05), strongly suggesting that the variant is benign. c.4121C>T has been reported in the literature as a variant of uncertain significance in at least one individual with a diagnosis or suspicion of Ehlers-Danlos Syndrome (e.g., Ilves_2023), however without strong evidence for causality (e.g., lack of co-segregation data). These report(s) do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 37427422). ClinVar contains an entry for this variant (Variation ID: 419573). Based on the evidence outlined above, the variant was classified as likely benign.