ClinVar Miner

Submissions for variant NM_000202.8(IDS):c.1006G>T (p.Gly336Trp) (rs1557338581)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548295 SCV000628119 likely pathogenic Mucopolysaccharidosis, MPS-II 2018-01-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with tryptophan at codon 336 of the IDS protein (p.Gly336Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. This variant also falls at the last nucleotide of exon 7 of the IDS coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a IDS-related disease. Two different variant affecting this nucleotide, c.1006G>C and c.1006G>A (both cause Gly to Arg change at codon 336) have been reported in individuals affected with Hunter disease (PMID: 17063374, 9266380, 8830188). In addition, other IDS missense changes affecting the same codon c.1007G>A (p.Gly336Glu) and c.1007G>T (p.Gly336Val) have also been reported in affected individuals (PMID: 24125893, 9660053). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098) and according to multiple splice site algorithms this particular variant may affect splicing. These predictions have not been confirmed by published functional studies. A different variant affecting this nucleotide (c.1006G>C) has been shown to disrupt RNA splicing and determined as likely pathogenic (PMID: 17063374, Invitae). This suggests that codon 336 is important for normal RNA processing and protein function, and that other variants at this position, such as c.1006G>T, may also be pathogenic. For these reasons, this variant has been classified as Likely Pathogenic.

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