Submissions for variant NM_000512.5(GALNS):c.871G>A (p.Ala291Thr)

gnomAD frequency: 0.00003  dbSNP: rs118204448

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000742	SCV001391923	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-07-29	criteria provided, single submitter	clinical testing	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. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 291 of the GALNS protein (p.Ala291Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IV (PMID: 7633425, 12721840, 15235041, 20574428). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 707). Experimental studies have shown that this missense change affects GALNS function (PMID: 12721840). This variant disrupts the p.Ala291 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been observed in individuals with GALNS-related conditions (PMID: 16287098, 25252036), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000000742	SCV001547817	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	curation	In vitro and in vivo functional studies supportive of a damaging effect on the gene product (low in vitro enzymatic activity; 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_moderate); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Genome-Nilou Lab	RCV000000742	SCV002045009	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	RCV003234884	SCV003934591	pathogenic	Morquio syndrome	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: GALNS c.871G>A (p.Ala291Thr) 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 229188 control chromosomes. c.871G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (example, Bunge_1997, Montao_2003, Tomatsu_2004, Bidchol_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Montao_2003). The most pronounced variant effect results in non-detectable lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase activity in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 25252036, 9298823, 12721840, 15235041). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000000742	SCV004236690	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-04-03	criteria provided, single submitter	clinical testing
OMIM	RCV000000742	SCV000020892	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2003-07-01	no assertion criteria provided	literature only
Molecular Biology Laboratory, Department of Zoology, Quaid-i-azam University	RCV000000742	SCV003845952	pathogenic	Mucopolysaccharidosis, MPS-IV-A		no assertion criteria provided	research