Submissions for variant NM_000393.5(COL5A2):c.322+8T>C

gnomAD frequency: 0.00026  dbSNP: rs372227642

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000124524	SCV000167957	benign	not specified	2014-05-27	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.
PreventionGenetics, part of Exact Sciences	RCV000124524	SCV000303996	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725338	SCV000336127	uncertain significance	not provided	2015-10-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000329201	SCV000425669	uncertain significance	Ehlers-Danlos syndrome type 7A	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV002228284	SCV000558983	likely benign	Ehlers-Danlos syndrome, classic type, 1	2024-01-19	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680518	SCV000807908	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001684	SCV001159239	likely benign	Ehlers-Danlos syndrome, classic type, 2	2018-12-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001001684	SCV001302442	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277243	SCV002565827	uncertain significance	Ehlers-Danlos syndrome	2019-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000124524	SCV003934489	benign	not specified	2023-05-10	criteria provided, single submitter	clinical testing	Variant summary: COL5A2 c.322+8T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational 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 0.00025 in 251100 control chromosomes. The observed variant frequency is approximately 40 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A2 causing Ehlers-Danlos Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.322+8T>C in individuals affected with Ehlers-Danlos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 . Multiple laboratories reported the variant with conflicting assessments: Likely Benign (n=4) and VUS (n=3). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000725338	SCV004148288	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	COL5A2: BP4
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000725338	SCV001932990	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725338	SCV001965310	likely benign	not provided		no assertion criteria provided	clinical testing