ClinVar Miner

Submissions for variant NM_000512.5(GALNS):c.337A>T (p.Ile113Phe) (rs118204438)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723431 SCV000230108 pathogenic not provided 2016-02-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000000738 SCV000399657 pathogenic Mucopolysaccharidosis, MPS-IV-A 2017-04-27 criteria provided, single submitter clinical testing The GALNS c.337A>T (p.Ile113Phe) missense variant is described as the second most frequently reported pathogenic variant, accounting for five percent of mucopolysaccharidosis type IV type A patient alleles (Morrone et al. 2014), and is especially common among patients of British and Irish descent. Across a selection of the available literature, the p.Ile113Phe variant has been identified in a homozygous state in two patients with mucopolysaccharidosis type IV, in a compound heterozygous state in 11 patients, and in a heterozygous state in six patients (Tomatsu et al. 1995; Yamada et al. 1998; Tomatsu et al. 2004; Dung et al. 2013; Bhattacharya et al. 2014). The p.Ile113Phe variant was absent from 300 control chromosomes (Tomatsu et al. 1995; Yamada et al. 1998; Tomatsu et al. 2004) and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project; however, this frequency is based on one allele only in a region of good sequence coverage, suggesting the variant is rare. In vitro transient expression studies showed that the p.Ile113Phe variant reduced cDNA expression to approximately five percent of wild type (Tomatsu et al. 1995; Sukegawa et al. 2000). Based on the collective evidence, the p.Ile113Phe variant is classified as pathogenic for mucopolysaccharidosis type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000295527 SCV000697064 pathogenic Morquio syndrome 2019-07-03 criteria provided, single submitter clinical testing Variant summary: GALNS c.337A>T (p.Ile113Phe) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250984 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GALNS causing Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (4e-05 vs 0.002), allowing no conclusion about variant significance. c.337A>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (Yamada_1998, Tomatsu_2004, Dung_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating the effects of the variant on protein function. The most pronounced variant effect results in <10% of normal activity (Yamada_1998, Sukegawa_2000). Two ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000000738 SCV001547666 likely pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter research In vivo and in vitro functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low in vitro enzymatic activity; PS3_moderate); 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)
Invitae RCV000000738 SCV001581551 pathogenic Mucopolysaccharidosis, MPS-IV-A 2020-06-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 113 of the GALNS protein (p.Ile113Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs118204438, ExAC 0.003%). This variant has been observed to be homozygous or in combination with another GALNS variant in several individuals affected with mucopolysaccharidosis type IVA (PMID: 7668283, 25137622, Invitae). ClinVar contains an entry for this variant (Variation ID: 703). This variant has been reported to affect GALNS protein function (PMID: 7668283). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000738 SCV000020888 pathogenic Mucopolysaccharidosis, MPS-IV-A 1998-01-01 no assertion criteria provided literature only
GeneReviews RCV000000738 SCV000086808 pathogenic Mucopolysaccharidosis, MPS-IV-A 2021-06-14 no assertion criteria provided literature only

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