ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.1156C>T (p.Arg386Cys) (rs118204437)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079019 SCV000225229 pathogenic not provided 2014-01-23 criteria provided, single submitter clinical testing
GeneDx RCV000079019 SCV000321695 pathogenic not provided 2018-02-12 criteria provided, single submitter clinical testing The R386C missense variant in the GALNS gene has been reported previously in association with ucopolysaccharidosis type IVA (MPS IVA). Patients homozygous for R386C are reported to have a severe MPS IVA phenotype (Tomatsu et al., 1997). This variant is located within the active site of the N-acetylgalactosamine-6-sulfatase enzyme (Rivera-Colon et al., 2012). R386C is the most prevalent GALNS variant having been reported on 8.9% of mutant alleles (Tomatsu et al., 2005).
DNA and Cytogenetics Diagnostics Unit,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 2019-09-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 386 of the GALNS protein (p.Arg386Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs118204437, ExAC 0.05%). This variant has been reported in several individuals affected with Morquio syndrome both in the homozygous state or in combination with other GALNS variants (PMID: 7795586, 26147980, 9298823, 23227063, 22976768, 24726177). ClinVar contains an entry for this variant (Variation ID: 700). Experimental studies have shown that this missense change abrogates GALNS enzymatic activity (PMID: 7795586, 15309681). A different missense substitution at this codon (p.Arg386Ser) has been reported as a compound heterozygous in an individual affected with Morquio syndrome (PMID: 25252036). 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)
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 pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-06-14 no assertion criteria provided literature only

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