Submissions for variant NM_000512.5(GALNS):c.268C>T (p.Arg90Trp)

gnomAD frequency: 0.00001  dbSNP: rs1028668536

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000624508	SCV000740807	pathogenic	Inborn genetic diseases	2014-12-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763388	SCV000894089	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-08-03	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000763388	SCV001547640	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_strong); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Genome-Nilou Lab	RCV000763388	SCV002045035	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
3billion	RCV000763388	SCV002058275	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000520618, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 27331011, 30458289, 24726177, PM3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.983, 3CNET: 0.998, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV003128664	SCV003805277	pathogenic	not provided	2022-08-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 31589614, 25501214, 25545067, 34387910, 30458289, 25287660, 22940367, 15235041, 27331011, 33752727, 24726177, 7633425, 25252036)
Invitae	RCV000763388	SCV004296422	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 90 of the GALNS protein (p.Arg90Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of GALNS-related conditions (PMID: 30458289). ClinVar contains an entry for this variant (Variation ID: 520618). 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 GALNS protein function with a positive predictive value of 95%. This variant disrupts the p.Arg90 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.