Submissions for variant NM_000093.5(COL5A1):c.1888C>T (p.Arg630Trp)

gnomAD frequency: 0.00011  dbSNP: rs577618553

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198923	SCV000249800	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with a COL5A1-related disorder to our knowledge; 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 (Symoens et al., 2012; HGMD); This variant is associated with the following publications: (PMID: 33206719)
Invitae	RCV002229042	SCV000631460	likely benign	Ehlers-Danlos syndrome, classic type, 1	2024-01-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000559592	SCV000897497	uncertain significance	Ehlers-Danlos syndrome, classic type	2018-10-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277474	SCV002565680	benign	Ehlers-Danlos syndrome	2021-09-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408861	SCV002723837	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-10-19	criteria provided, single submitter	clinical testing	The p.R630W variant (also known as c.1888C>T), located in coding exon 18 of the COL5A1 gene, results from a C to T substitution at nucleotide position 1888. The arginine at codon 630 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a whole exome sequencing cohort of COVID-19 patients (Benetti E et al. PLoS One, 2020 Nov;15:e0242534). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000198923	SCV004564739	uncertain significance	not provided	2023-04-27	criteria provided, single submitter	clinical testing	The COL5A1 c.1888C>T; p.Arg630Trp variant (rs577618553), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 212944). This variant is found in the non-Finnish European population with an allele frequency of 0.02% (25/128836 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.85). Due to limited information, the clinical significance of this variant is uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525898	SCV005039330	likely benign	not specified	2024-03-13	criteria provided, single submitter	clinical testing	Variant summary: COL5A1 c.1888C>T (p.Arg630Trp) 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 0.0001 in 251012 control chromosomes. The observed variant frequency is approximately 3.19 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. To our knowledge, no occurrence of c.1888C>T 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: 212944). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000198923	SCV005050831	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	COL5A1: PP3, BS1
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000198923	SCV001929905	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000198923	SCV001973477	uncertain significance	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV002229042	SCV004101128	uncertain significance	Ehlers-Danlos syndrome, classic type, 1	2023-11-02	no assertion criteria provided	clinical testing