Submissions for variant NM_000093.5(COL5A1):c.1831C>T (p.Arg611Trp)

gnomAD frequency: 0.00006  dbSNP: rs147329970

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001705094	SCV000249799	uncertain significance	not provided	2024-05-24	criteria provided, single submitter	clinical testing	Has not been previously reported as pathogenic or benign in association with cEDS to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the X 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 X position is not a common mechanism of disease (PMID: 22696272; HGMD); This variant is associated with the following publications: (PMID: 29924831, 32938213, 36043395, 33161638)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228843	SCV000755928	likely benign	Ehlers-Danlos syndrome, classic type, 1	2024-10-12	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002228843	SCV002767922	uncertain significance	Ehlers-Danlos syndrome, classic type, 1	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with classic type Ehlers-Danlos syndrome 1 (MIM#130000). Dominant negative is a suggested mechanism of disease (PMID: 32720758). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2 & v3: 28 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 20 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated triple helical domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg611Gln) has been reported as a VUS, including in an individual with suspected aortopathy (ClinVar, VCGS). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a VUS, including in three affected individuals (ClinVar, VCGS, PMID: 32938213). It has also been reported in an individual with classic Ehlers-Danlos syndrome (PMID: 33161638). However, it has also been reported as likely benign once in ClinVar without further information provided. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV001705094	SCV003917731	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing	COL5A1: PP3
Ambry Genetics	RCV004609323	SCV005106040	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-04-11	criteria provided, single submitter	clinical testing	The p.R611W variant (also known as c.1831C>T), located in coding exon 17 of the COL5A1 gene, results from a C to T substitution at nucleotide position 1831. The arginine at codon 611 is replaced by tryptophan, an amino acid with dissimilar 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. Based on the available evidence, the clinical significance of this variant remains unclear.
GenomeConnect, ClinGen	RCV001249369	SCV001423358	not provided	Ehlers-Danlos syndrome, classic type, 2; Ehlers-Danlos syndrome, classic type		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 07-18-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.