Submissions for variant NM_000202.8(IDS):c.806A>T (p.Asp269Val)

dbSNP: rs1085308006

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489884	SCV000577821	likely pathogenic	not provided	2015-04-27	criteria provided, single submitter	clinical testing	The D269V variant in the IDS gene has been reported in a patient with mucopolysaccharidosis type II (MPS II) (Karsten et al., 1998). The D269V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D269V variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (W264D, N265I, N265K, P266H, P266R, and W267C) have been reported in the Human Gene Mutation Database in association with MPS II (Stenson et al., 2014), supporting the functional importance of this region of the protein. The D269V variant is a strong candidate for a disease-causing variant. However, the possibility it may be a rare benign variant cannot be excluded.
Ambry Genetics	RCV002420251	SCV002677559	likely pathogenic	Inborn genetic diseases	2017-05-08	criteria provided, single submitter	clinical testing	The p.D269V variant (also known as c.806A>T), located in coding exon 6 of the IDS gene, results from an A to T substitution at nucleotide position 806. The aspartic acid at codon 269 is replaced by valine, an amino acid with highly dissimilar properties. This mutation was identified in two unrelated Portuguese individuals with Hunter syndrome. In addition, this study also demonstrated reduced mRNA levels and IDS enzyme activity in fibroblasts from an affected individual (Alves S et al. J. Inherit. Metab. Dis., 2006 Dec;29:743-54). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001376700	SCV005089252	likely pathogenic	Mucopolysaccharidosis, MPS-II	2024-06-07	criteria provided, single submitter	literature only	De novo (PS2_Moderate), In vitro or in vivo functional studies supportive of a damaging effect (PS3_Moderate), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Supporting), 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_Moderate)
Pediatrics, All India Institute of Medical Sciences, New Delhi	RCV001376700	SCV001573771	affects	Mucopolysaccharidosis, MPS-II	2014-04-02	no assertion criteria provided	research	The change c.806A>T (p.D269V) was found to be a missense variant, where the acidic polar negative amino acid Aspartic acid at 269 position was substituted by aliphatic nonpolar neutral amino acid Valine. It was detected in a hemizygous state in a single patient with attenuated phenotype from Rajasthan.