Submissions for variant NM_001853.4(COL9A3):c.388G>A (p.Gly130Ser)

gnomAD frequency: 0.00096  dbSNP: rs139401633

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726919	SCV000536260	uncertain significance	not provided	2024-02-12	criteria provided, single submitter	clinical testing	Reported in association with age-related macular degeneration and unspecified retinal and optical nerve disorders (PMID: 24036952); Reported to segregate with autosomal dominant disease in a family with bilateral vitreoretinal lattice degeneration (PMID: 33633367); 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: 32483926, 35241111, 36621380, 24036952, 33633367)
Eurofins Ntd Llc (ga)	RCV000726919	SCV000704160	uncertain significance	not provided	2016-12-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764251	SCV000895256	uncertain significance	Epiphyseal dysplasia, multiple, 3; Intervertebral disc disorder	2021-12-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726919	SCV001153510	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	COL9A3: PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726919	SCV001532577	uncertain significance	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the COL9A3 protein (p.Gly130Ser). This variant is present in population databases (rs139401633, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal dominant vitreoretinal degeneration and/or blindness (PMID: 32483926, 33633367). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 392918). 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) performed at Invitae indicates that this missense variant is expected to disrupt COL9A3 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279225	SCV002566442	uncertain significance	Connective tissue disorder	2020-01-01	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000726919	SCV005195069	uncertain significance	not provided		criteria provided, single submitter	not provided
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786719	SCV005399128	uncertain significance	Epiphyseal dysplasia, multiple, 3	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stickler syndrome and epiphyseal dysplasia, with or without myopathy (MIM#600969). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive inheritance is associated with Stickler syndrome (PMIDs: 24273071, 31090205), while autosomal dominant inheritance is associated with multiple epiphyseal dysplasia, with or without myopathy, and more recently with isolated deafness and retinal phenotypes that overlap with Stickler syndrome (PMID: 33633367). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra- and inter-familial phenotypic variability has been observed in individuals with multiple epiphyseal dysplasia (PMID: 20301302). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (228 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located at a glycine position within a G-X-Y triple helical repeat (DECIPHER, PMID: 33633367). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a VUS five times by clinical laboratories in ClinVar, and once as likely pathogenic in a family with vitreoretinal degeneration and reitinal detachment (PMID: 33633367). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Eye Genetics Research Group, Children's Medical Research Institute	RCV001283726	SCV001424846	likely pathogenic	Retinal detachment; Lattice retinal degeneration	2020-07-22	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925303	SCV004740468	likely benign	COL9A3-related disorder	2021-03-02	no assertion criteria provided	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).