Submissions for variant NM_000393.5(COL5A2):c.1081A>C (p.Met361Leu)

gnomAD frequency: 0.01714  dbSNP: rs76148000

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000124494	SCV000167927	benign	not specified	2013-02-25	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205728	SCV000261989	benign	Ehlers-Danlos syndrome, classic type, 1	2025-02-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000124494	SCV000303972	benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000124494	SCV000337383	benign	not specified	2015-11-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000345304	SCV000425655	likely benign	Ehlers-Danlos syndrome type 7A	2016-06-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999725	SCV000603199	benign	Ehlers-Danlos syndrome, classic type, 2	2024-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586971	SCV000696668	benign	not provided	2017-03-21	criteria provided, single submitter	clinical testing	Variant summary: The COL5A2 c.1081A>C (p.Met361Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 3/3 in silico tools predict a benign outcome (SNPs&GO and MutationTaster not captured here due to low reliability index and p-value, respectively). This variant has been observed in a large, broad control population, ExAC, in 2216/120978 control chromosomes (38 homozygotes) at a frequency of 0.0183174, which is approximately 2931 times the estimated maximal expected allele frequency of a pathogenic COL5A2 variant (0.0000063), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Ambry Genetics	RCV002312855	SCV000738331	benign	Familial thoracic aortic aneurysm and aortic dissection	2015-02-06	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Illumina Laboratory Services, Illumina	RCV000999725	SCV001300420	benign	Ehlers-Danlos syndrome, classic type, 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277229	SCV002565796	benign	Ehlers-Danlos syndrome	2022-05-21	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000586971	SCV005255908	likely benign	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000124494	SCV001807581	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000124494	SCV001930509	benign	not specified		no assertion criteria provided	clinical testing