Submissions for variant NM_000199.5(SGSH):c.817G>A (p.Asp273Asn)

gnomAD frequency: 0.00001  dbSNP: rs1046551417

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668913	SCV000793588	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2017-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781846	SCV000920208	uncertain significance	not specified	2021-01-15	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.817G>A (p.Asp273Asn) results in a conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250174 control chromosomes (gnomAD) and been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Beesley_2000, Truxal_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, based on the atomic structure of SGSH, Sidhu et. al. report that this variant may disrupts Ca2+ binding (Sidhu_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae	RCV000668913	SCV000947471	pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-11-29	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 553454). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 11182930, 27590925; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 273 of the SGSH protein (p.Asp273Asn). 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 SGSH protein function. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000668913	SCV002045094	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000668913	SCV002583840	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-08-08	criteria provided, single submitter	clinical testing	A compound heterozygous missense variation in exon 7 of the SGSH gene that results in the amino acid substitution of Histidine for Arginine at codon 377 was detected. The observed variant has a minor allele frequency of 0.0003%, and 0.0008% in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is benign by DANN, SIFT, LRT ,FATHMM-XF, MutPred and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a likely pathogenic variant.
Molecular Biology Laboratory, Department of Zoology, Quaid-i-azam University	RCV000668913	SCV004012875	likely pathogenic	Mucopolysaccharidosis, MPS-III-A		no assertion criteria provided	research