Submissions for variant NM_001854.4(COL11A1):c.4547G>T (p.Gly1516Val)

dbSNP: rs1553193910

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000591257	SCV000704000	pathogenic	not provided	2018-07-23	criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000624108	SCV000740282	likely pathogenic	Marshall syndrome	2017-11-09	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV001799515	SCV001739307	pathogenic	Marshall syndrome; Stickler syndrome type 2; Hearing loss, autosomal dominant 37	2020-09-11	criteria provided, single submitter	clinical testing
DASA	RCV001824151	SCV002073773	likely pathogenic	Stickler syndrome type 2	2022-02-05	criteria provided, single submitter	clinical testing	The c.4547G>T;p.(Gly1516Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 20513134) - PS4_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (collagen helix of α1(XI) collagen) - PM1. This variant is not present in population databases (rs1553193910; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000591257	SCV005833985	pathogenic	not provided	2024-08-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1516 of the COL11A1 protein (p.Gly1516Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Stickler syndrome (PMID: 10486316, 20513134; Invitae). This variant is also known as G988V. ClinVar contains an entry for this variant (Variation ID: 498797). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL11A1 protein function. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004737861	SCV005365990	pathogenic	COL11A1-related disorder	2024-04-26	no assertion criteria provided	clinical testing	The COL11A1 c.4547G>T variant is predicted to result in the amino acid substitution p.Gly1516Val. This variant has been reported in two individuals with Marshall/Stickler syndrome/isolated hearing loss (reported as G988V; Annunen et al. 1999. PubMed ID: 10486316; reported as de novo, Van Heurck et al. 2021. PubMed ID: 34440452). This variant affects a Gly residue of the conserved Gly-Xaa-Yaa triple helical domain (amino acid residues 529-1542, www.uniprot.org/uniprotkb/P12107/), where substitutions of glycine are usually pathogenic (Richards et al. 2010. PubMed ID: 20513134; https://www.ncbi.nlm.nih.gov/books/NBK1302/). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic.