Submissions for variant NM_000512.5(GALNS):c.953T>G (p.Met318Arg)

gnomAD frequency: 0.00001  dbSNP: rs746756997

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180514	SCV000232972	pathogenic	not provided	2014-10-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624404	SCV000742738	pathogenic	Inborn genetic diseases	2017-08-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193735	SCV001362797	pathogenic	Morquio syndrome	2019-05-10	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.953T>G (p.Met318Arg) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250646 control chromosomes (gnomAD). The variant, c.953T>G, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Ogawa_1995, Morrone_2014, Xie_2019). These data indicate that the variant is very likely to be associated with disease. One publication, Ogawa_1995, showed that transfected GALNS activity of this variant was <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001389837	SCV001547857	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	In vitro and in vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; 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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389837	SCV001591346	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-09-16	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 318 of the GALNS protein (p.Met318Arg). This variant is present in population databases (rs746756997, gnomAD 0.04%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 23876334, 24035930, 30458289). ClinVar contains an entry for this variant (Variation ID: 199031). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GALNS protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001389837	SCV002045005	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001389837	SCV005417702	pathogenic	Mucopolysaccharidosis, MPS-IV-A		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PM3_VeryStrong+PP4
Fulgent Genetics, Fulgent Genetics	RCV001389837	SCV005641469	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-03-22	criteria provided, single submitter	clinical testing