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

gnomAD frequency: 0.00006  dbSNP: rs118204437

Total submissions: 13

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
Invitae	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
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