Submissions for variant NM_000093.5(COL5A1):c.514G>T (p.Val172Phe)

dbSNP: rs150147262

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199784	SCV000249872	uncertain significance	not provided	2024-03-27	criteria provided, single submitter	clinical testing	Reported in a patient with bleeding diathesis, hypermobility, and at least one first degree family member with bleeding diathesis who also harbored the p.(R65W) variant in the COL5A1 gene (PMID: 33161638); Reported in a patient with Ehlers-Danlos syndrome, a patient with vertebral artery dissection who also harbored the p.(R65W) variant in the COL5A1 gene, and in a case of sudden infant death syndrome (SIDS) (PMID: 30858776, 31903434, 28074886); Not located in the triple helical region, where the majority of pathogenic missense variants occur (PMID: 22696272; HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31903434, 33161638, 30858776, 35723357, 36043395, 22696272, 28074886)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229378	SCV000631540	likely benign	Ehlers-Danlos syndrome, classic type, 1	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313004	SCV000738565	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-09-30	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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659439	SCV000781253	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000199784	SCV001155816	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	COL5A1: BP4, BS2
Illumina Laboratory Services, Illumina	RCV001085122	SCV001329746	likely benign	Ehlers-Danlos syndrome, classic type	2018-01-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235074	SCV003934213	likely benign	not specified	2024-06-04	criteria provided, single submitter	clinical testing	Variant summary: COL5A1 c.514G>T (p.Val172Phe) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 250454 control chromosomes, predominantly at a frequency of 0.0007 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 22-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A1 causing Ehlers-Danlos Syndrome phenotype (3.1e-05). The variant, c.514G>T, has been reported in the literature in individuals affected with Ehlers-Danlos Syndrome (Junkiert-Czarnecka_2019), Cervical Artery Dissection (Traenka_2019) and Keratoconus (Fransen_2021), but was also found in multiple healthy controls (Fransen_2021). These reports 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 publications have been ascertained in the context of this evaluation (PMID: 30858776, 28074886, 31903434, 33737726). ClinVar contains an entry for this variant (Variation ID: 180298). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003907484	SCV004735455	likely benign	COL5A1-related disorder	2023-08-17	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).
Blueprint Genetics	RCV000157144	SCV000206867	uncertain significance	Aortic valve disease 1; Familial thoracic aortic aneurysm and aortic dissection	2014-04-08	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000199784	SCV001808838	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000199784	SCV001931512	likely benign	not provided		no assertion criteria provided	clinical testing