rs1557338581
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000202.8(IDS):c.1006G>T(p.Gly336Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G336E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000202.8 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDS | NM_000202.8 | c.1006G>T | p.Gly336Trp | missense_variant, splice_region_variant | 7/9 | ENST00000340855.11 | |
IDS | NM_001166550.4 | c.736G>T | p.Gly246Trp | missense_variant, splice_region_variant | 7/9 | ||
IDS | NM_006123.5 | c.1006G>T | p.Gly336Cys | missense_variant, splice_region_variant | 7/8 | ||
IDS | NR_104128.2 | n.1305G>T | splice_region_variant, non_coding_transcript_exon_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDS | ENST00000340855.11 | c.1006G>T | p.Gly336Trp | missense_variant, splice_region_variant | 7/9 | 1 | NM_000202.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-II Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2018 | For these reasons, this variant has been classified as Likely Pathogenic. 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. 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. 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). 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at