Submissions for variant NM_000393.5(COL5A2):c.5T>C (p.Met2Thr)

gnomAD frequency: 0.00001  dbSNP: rs762874073

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200003	SCV000250001	uncertain significance	not provided	2024-06-20	criteria provided, single submitter	clinical testing	Reported in a patient with classic Ehlers-Danlos syndrome who also harbored the p.(P659L) variant in COL5A2 (PMID: 33161638); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (PMID: 22696272; HGMD); This variant is associated with the following publications: (PMID: 22696272, 33161638)
Ambry Genetics	RCV002311048	SCV000320325	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2025-01-07	criteria provided, single submitter	clinical testing	The p.M2T variant (also known as c.5T>C), located in coding exon 1 of the COL5A2 gene, results from a T to C substitution at nucleotide position 5. The methionine at codon 2 is replaced by threonine, an amino acid with similar 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229099	SCV000631612	likely benign	Ehlers-Danlos syndrome, classic type, 1	2025-02-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000200003	SCV001250015	uncertain significance	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000200003	SCV001713257	uncertain significance	not provided	2020-06-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767138	SCV005381396	likely benign	not specified	2024-08-05	criteria provided, single submitter	clinical testing	Variant summary: COL5A2 c.5T>C (p.Met2Thr) 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 4.7e-05 in 234428 control chromosomes. The observed variant frequency is approximately 7.51 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A2 causing Ehlers-Danlos Syndrome phenotype (6.3e-06). To our knowledge, no occurrence of c.5T>C 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: 213138). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV005230056	SCV005876052	uncertain significance	Ehlers-Danlos syndrome, classic type, 2	2024-11-22	criteria provided, single submitter	clinical testing	The COL5A2 c.5T>C; p.Met2Thr variant (rs762874073; ClinVar ID: 213138) is reported in the literature in an individual with a bleeding disorder (Fager Ferrari 2021), although to our knowledge it has not been reported in association with an aortopathy disorder. This variant is found in the non-Finnish European population with an allele frequency of 0.009% (9/103,342 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.601). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Fager Ferrari M et al. Collagen remodelling and plasma ascorbic acid levels in patients suspected of inherited bleeding disorders harbouring germline variants in collagen-related genes. Haemophilia. 2021 Jan;27(1):e69-e77. PMID: 33161638.
PreventionGenetics, part of Exact Sciences	RCV004748650	SCV005362406	uncertain significance	COL5A2-related disorder	2024-08-12	no assertion criteria provided	clinical testing	The COL5A2 c.5T>C variant is predicted to result in the amino acid substitution p.Met2Thr. To our knowledge, this variant was reported as a variant of uncertain significance in a cohort of patients with bleeding disorders (Leinøe et al. 2017. PubMed ID: 28748566). This variant is reported in 0.011% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-190044326-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.