ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.1197C>G (p.Phe399Leu)

dbSNP: rs200793396
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000677462 SCV000802969 likely pathogenic Mucopolysaccharidosis type 6 2018-01-01 criteria provided, single submitter curation In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAC (PM2)
Illumina Laboratory Services, Illumina RCV000677462 SCV000915136 pathogenic Mucopolysaccharidosis type 6 2018-09-10 criteria provided, single submitter clinical testing The ARSB c.1197C>G (p.Phe399Leu) missense variant has been reported in five studies and is found in a total of seven individuals with mucopolysaccharidosis, type VI, including in one in a homozygous state and in six in a compound heterozygous state, including one sibling pair (Yang et al. 2001; Ching-Wan et al. 2004; Lin et al. 2008; But et al. 2011; Zheng et al. 2014). The p.Phe399Leu variant was also found in a heterozygous state in two unaffected parents (Ching-Wan et al. 2004). The p.Phe399Leu variant was absent from 150 control subjects and is reported at a frequency of 0.000174 in the East Asian population of the Genome Aggregation Database. Based on the evidence, the p.Phe399Leu variant is classified as pathogenic for mucopolysaccharidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000677462 SCV001221173 pathogenic Mucopolysaccharidosis type 6 2023-09-13 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 399 of the ARSB protein (p.Phe399Leu). This variant is present in population databases (rs200793396, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 11802522, 18486607, 25190157). ClinVar contains an entry for this variant (Variation ID: 559688). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARSB protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000677462 SCV004206771 pathogenic Mucopolysaccharidosis type 6 2023-10-02 criteria provided, single submitter clinical testing

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