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

gnomAD frequency: 0.00006  dbSNP: rs147329970

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001705094	SCV000249799	uncertain significance	not provided	2023-02-09	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 (Symoens et al., 2012; HGMD); This variant is associated with the following publications: (PMID: 29924831, 32938213, 36043395, 33161638)
Invitae	RCV002228843	SCV000755928	likely benign	Ehlers-Danlos syndrome, classic type, 1	2023-09-18	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
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.