ClinVar Miner

Submissions for variant NM_000202.8(IDS):c.133G>C (p.Asp45His)

dbSNP: rs869025301
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
MOLECULAR BIOLOGY LABORATORY, INSTITUTO NACIONAL DE PEDIATRIA RCV000207419 SCV000262703 likely pathogenic Mucopolysaccharidosis, MPS-II 2015-10-18 criteria provided, single submitter research Likely pathogenic variation identified in a Hunter syndrome male patient without I2S evaluation. He presents mental retardation and seizures. No hydrocephaly. Pathogenicity clues: Highly conserved nucleotide (phyloP: 0.86 [-5.2;1.1]); Highly conserved amino acid, up to Fruitfly (considering 12 species); Moderate physicochemical difference between Asp and His (Grantham dist.: 81 [0-215]); This variant is in protein domains: Sulfatase, Alkaline-phosphatase-like, core domain, Align GVGD: C0 (GV: 213.16 - GD: 59.84); SIFT: Deleterious (score: 0, median: 3.50); MutationTaster: disease causing (p-value: 1); Polyphen prediction: Probably Damaging (HumDiv score 1.0)
Labcorp Genetics (formerly Invitae), Labcorp RCV000207419 SCV001576860 pathogenic Mucopolysaccharidosis, MPS-II 2022-01-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp45 amino acid residue in IDS. Other variant(s) that disrupt this residue have been observed in individuals with IDS-related conditions (PMID: 9875019, 24125893), which suggests that this may be a clinically significant amino acid residue. 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) performed at Invitae indicates that this missense variant is expected to disrupt IDS protein function. ClinVar contains an entry for this variant (Variation ID: 221970). This missense change has been observed in individual(s) with mucopolysaccharidosis type II (PMID: 26762690; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 45 of the IDS protein (p.Asp45His).
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000207419 SCV005089243 pathogenic Mucopolysaccharidosis, MPS-II 2024-06-07 criteria provided, single submitter literature only Located in a mutational hot spot and/or critical functional domain (PM1_Moderate), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Strong)

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