Submissions for variant NM_000512.5(GALNS):c.1156C>T (p.Arg386Cys)

gnomAD frequency: 0.00006  dbSNP: rs118204437

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079019	SCV000225229	pathogenic	not provided	2014-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000079019	SCV000321695	pathogenic	not provided	2022-02-07	criteria provided, single submitter	clinical testing	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: 15309681, 23401410, 25287660, 15241807, 10814710, 23876334, 15235041, 25137622, 12442278, 26502894, 7795586, 8829629, 24726177, 16287098, 22940367, 30927141, 34426522, 31589614, 34896230, 33636292, 9375852, 9298823, 34504088)
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000000735	SCV000745324	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2015-09-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000735	SCV000831519	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 386 of the GALNS protein (p.Arg386Cys). This variant is present in population databases (rs118204437, gnomAD 0.05%). This missense change has been observed in individuals with Morquio syndrome (PMID: 7795586, 9298823, 22976768, 23227063, 24726177, 26147980). ClinVar contains an entry for this variant (Variation ID: 700). 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%. Experimental studies have shown that this missense change affects GALNS function (PMID: 7795586, 15309681). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781397	SCV000919394	pathogenic	Morquio syndrome	2017-12-04	criteria provided, single submitter	clinical testing	Variant summary: The GALNS c.1156C>T (p.Arg386Cys) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study, Fukuda_1996, supports these predictions with the observation that the variant causes deficient GALNS activity. This variant was found in 23/275538 control chromosomes (gnomAD) at a frequency of 0.0000835, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALNS variant (0.0020412). Multiple publications have cited the variant in affected homozygous and compound heterozygous pts. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV000000735	SCV001528502	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2018-03-01	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 7795586, 8829629, 25287660, 22940367]
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000000735	SCV001547906	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-02-01	criteria provided, single submitter	research	De novo (both maternity and paternity confirmed) in a patient with the disease and no family history (PS2_strong); 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); cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1_supporting); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Revvity Omics, Revvity	RCV000000735	SCV002024160	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2023-06-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000000735	SCV002044999	likely pathogenic	Mucopolysaccharidosis, MPS-IV-A	2021-11-07	criteria provided, single submitter	clinical testing
Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital	RCV000000735	SCV004697581	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2022-02-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000781397	SCV004847431	pathogenic	Morquio syndrome	2024-02-02	criteria provided, single submitter	clinical testing	The p.Arg392Cys variant in GALNS has been reported in the homozygous or heterozygous state in >12 individuals (>4 homozygotes, >8 compound heterozygotes) with mucopolysaccharidosis type 4A (MPS 4A). At least 2 of these individuals underwent biochemical analyses that showed markedly reduced GALNS enzyme activity (Ogawa 1995 PMID: 7795586, Bunge 1997 PMID: 9298823, Lee 2012 PMID: 23227063, Pollard 2013 PMID: 22976768, Morrone 2014 PMID: 24726177, Jazela-Stanek 2019 PMID: 30927141, Fang 2022 PMID: 34813777). This variant segregated with disease in at least 2 affected relatives from 2 families (Jazela-Stanek 2019 PMID: 30927141). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 700) and has been identified in 0.03% (4/15280) of Latino/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This frequency is consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that this variant reduces GALNS activity (Ogawa 1995 PMID: 7795586) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive mucopolysaccharidosis type 4A. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Moderate, PM2_Supporting, PP3, PS3_Supporting, PP4.
Neuberg Centre For Genomic Medicine, NCGM	RCV000000735	SCV005373671	uncertain significance	Mucopolysaccharidosis, MPS-IV-A	2023-05-20	criteria provided, single submitter	clinical testing	The missense c.1156C>T (p.Arg386Cys) variant in the GALNS gene has been observed in individuals with Morquio syndrome (Cozma, Claudia et al.,2015). Experimental studies have shown that this missense change affects GALNS function (Tomatsu, Shunji et al., 2004). This variant is reported with the allele frequency (0.008%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Arginine at position 386 is changed to a Cystine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid Glycine in GALNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000000735	SCV000020885	pathogenic	Mucopolysaccharidosis, MPS-IV-A	2004-01-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000000735	SCV000733545	pathogenic	Mucopolysaccharidosis, MPS-IV-A		no assertion criteria provided	clinical testing
GeneReviews	RCV000000735	SCV001761899	not provided	Mucopolysaccharidosis, MPS-IV-A		no assertion provided	literature only