Submissions for variant NM_000199.5(SGSH):c.703G>A (p.Asp235Asn)

gnomAD frequency: 0.00005  dbSNP: rs753472891

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668365	SCV000792951	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-07-27	criteria provided, single submitter	clinical testing
Invitae	RCV000668365	SCV000963681	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 235 of the SGSH protein (p.Asp235Asn). This variant is present in population databases (rs753472891, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 11182930, 12000360, 19099774; Invitae). ClinVar contains an entry for this variant (Variation ID: 553004). 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. Experimental studies have shown that this missense change affects SGSH function (PMID: 12000360). This variant disrupts the p.Asp235 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 9401012), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000668365	SCV002045496	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668365	SCV002547900	pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-05-11	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.703G>A (p.Asp235Asn) 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 1.7e-05 in 237402 control chromosomes (gnomAD). c.703G>A has been reported in the literature in compound heterozygous individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Beesley_2000, Lee-Chen_2002, Heron_2011). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon (Asp235Val) has been reported in affected individuals, suggesting this may be an important residue (Beesley_2000). One publication reports that the variant protein has 1.7% N-Sulphatase activity (Lee-Chen_2002). Three ClinVar submitters have assessed the variant since 2014: two classify the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003420182	SCV004118381	pathogenic	SGSH-related condition	2022-10-13	criteria provided, single submitter	clinical testing	The SGSH c.703G>A variant is predicted to result in the amino acid substitution p.Asp235Asn. This variant along with a second variant in SGSH was reported in multiple individuals with Sanfilippo syndrome IIIA (also known as Sanfilippo A) (Beesley et al. 2000. PubMed ID: 11182930; Zhang et al. 2008. PubMed ID: 19099774; Lee-Chen et al. 2002. PubMed ID: 12000360; Table S2, Héron et al. 2011. PubMed ID: 21204211; Delgadillo et al. 2013. PubMed ID: 24314109). In addition, a different variant affecting the same amino acid (p.Asp235Val) was reported to be pathogenic for Sanfilippo syndrome A (Bunge et al. 1997. PubMed ID: 9401012). Structure and computational predication studies suggest this variant disrupts enzyme activity (Sidhu et al. 2014. PubMed ID: 24816101; Ugrinov et al. 2015. PubMed ID: 25807448). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78187645-C-T). This variant is interpreted as pathogenic.
Baylor Genetics	RCV000668365	SCV004201077	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-10-14	criteria provided, single submitter	clinical testing