Submissions for variant NM_000202.8(IDS):c.253G>A (p.Ala85Thr)

dbSNP: rs113993949

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790731	SCV000228820	pathogenic	not provided	2012-09-05	criteria provided, single submitter	clinical testing
IIFP, CONICET-UNLP	RCV000177016	SCV000262519	pathogenic	Mucopolysaccharidosis, MPS-II	2007-05-16	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000177016	SCV000919530	pathogenic	Mucopolysaccharidosis, MPS-II	2018-08-17	criteria provided, single submitter	clinical testing	Variant summary: IDS c.253G>A (p.Ala85Thr) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 169233 control chromosomes (gnomAD). c.253G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome)(Alkhzouz_2016, Amartino_2014, Dvorakova_2017, Kosuga_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Alkhzouz_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	RCV000177016	SCV001479333	pathogenic	Mucopolysaccharidosis, MPS-II		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000177016	SCV002014484	pathogenic	Mucopolysaccharidosis, MPS-II	2021-09-05	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000177016	SCV002053783	pathogenic	Mucopolysaccharidosis, MPS-II		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000177016	SCV003445854	pathogenic	Mucopolysaccharidosis, MPS-II	2022-06-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 92617). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects IDS function (PMID: 17091340). 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. This missense change has been observed in individual(s) with mucopolysaccharidosis II (PMID: 8940265, 25976201, 26762690, 31877959). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 85 of the IDS protein (p.Ala85Thr).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000177016	SCV003807057	pathogenic	Mucopolysaccharidosis, MPS-II	2023-01-29	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PP1 supporting, PP3 supporting, PP4
Revvity Omics, Revvity	RCV000177016	SCV003829533	likely pathogenic	Mucopolysaccharidosis, MPS-II	2022-11-10	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000177016	SCV005088932	pathogenic	Mucopolysaccharidosis, MPS-II	2024-06-07	criteria provided, single submitter	literature only	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_Strong), 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	RCV000177016	SCV001573770	affects	Mucopolysaccharidosis, MPS-II	2014-04-01	no assertion criteria provided	research	The change c.253G>A, (p.A85T) was found to be a known missense variant, where the non-polar amino acid Alanine at 85 position was substituted with another polar amino acid Threonine. Uttarilli et al., described it in MPS II patients with attenuated phenotype from Kerala and Karnataka (Uttarilli et al.,2016). Rathmann et al., described A85T initially in one European MPS-II patients with attenuated phenotype (Rathmann et al.,1982). In our study, it was detected in the hemizygous condition in patients with MPS-II attenuated phenotype, hails from from the state of UP and Bihar, India.