Submissions for variant NM_000512.5(GALNS):c.1019G>A (p.Gly340Asp)

dbSNP: rs267606838

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centogene AG - the Rare Disease Company	RCV000000750	SCV001426611	pathogenic	Mucopolysaccharidosis, MPS-IV-A		criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000000750	SCV001547876	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); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Invitae	RCV000000750	SCV001591345	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 340 of the GALNS protein (p.Gly340Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 15235041, 20574428, 30458289, 30980944). ClinVar contains an entry for this variant (Variation ID: 18403). 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%. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000000750	SCV001984834	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2020-07-28	criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous and homozygous change in patients with Mucopolysaccharidosis IVA (PMID: 20574428, 15235041, 30980944, 30458289). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1019G>A (p.Gly340Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1019G>A (p.Gly340Asp) variant is classified as Likely Pathogenic.
Genome-Nilou Lab	RCV000000750	SCV002045002	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155036	SCV003844258	pathogenic	Morquio syndrome	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.1019G>A (p.Gly340Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 192834 control chromosomes. c.1019G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Tomatsu_2004, Wang_2010, Cozma_2015), and some are reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports quantification of GALNS enzymatic product using blood samples from MPS IVA affected patients and normal controls, finding that samples from patients homozygous with the variant showed a nearly complete loss of activity (Cozma_2015). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000000750	SCV000020900	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2010-08-01	no assertion criteria provided	literature only