Submissions for variant NM_000199.5(SGSH):c.1105G>A (p.Glu369Lys)

gnomAD frequency: 0.00001  dbSNP: rs104894640

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078349	SCV000232480	pathogenic	not provided	2013-08-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000078349	SCV000582578	pathogenic	not provided	2015-09-03	criteria provided, single submitter	clinical testing	The E369K variant in the SGSH gene has been reported previously in association with mucopolysaccharidosis IIIA (MPS IIIA) (Di Natale et al., 1998; Weber et al., 1997). Two individuals who were compound heterozygous for E369K and a different variant were reported to have a mild-intermediate phenotype (Di Natale et al., 1998; Esposito et al., 2000). In comparison with the wild type, E369K yielded similar molecular size and stability on western blot with the authors predicting the variant does not cause a dramatic change to the protein structure and function (Esposito et al., 2000). Therefore, we interpret E369K as a pathogenic variant.
Counsyl	RCV000005424	SCV000790783	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-05-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005424	SCV002015101	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-10-28	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.1105G>A (p.Glu369Lys) results in a conservative amino acid change in 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 4e-06 in 250408 control chromosomes (gnomAD). c.1105G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (e.g. Di Natale_1998, Esposito_2000, Valstar_2010, Heron_2011). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant considerably decreases or abolishes enzyme activity (Esposito_2000, Heron_2011). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000005424	SCV002045489	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000005424	SCV002153863	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-04-09	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 5117). This missense change has been observed in individual(s) with Sanfilippo syndrome (PMID: 9554748, 10727844, 12702166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894640, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 369 of the SGSH protein (p.Glu369Lys). 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. Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844).
Baylor Genetics	RCV000005424	SCV004201075	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-10-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894791	SCV004715469	likely pathogenic	SGSH-related condition	2023-11-13	criteria provided, single submitter	clinical testing	The SGSH c.1105G>A variant is predicted to result in the amino acid substitution p.Glu369Lys. This variant has been reported along with a second SGSH variant in individuals with Sanfilippo syndrome A (Di Natale et al. 1998. PubMed ID: 9554748; Esposito et al. 2000. PubMed ID: 10727844; Di Natale et al. 2003. PubMed ID: 12702166). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78184655-C-T). This variant is interpreted as likely pathogenic.
OMIM	RCV000005424	SCV000025606	pathogenic	Mucopolysaccharidosis, MPS-III-A	2003-04-01	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078349	SCV002037374	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078349	SCV002037805	pathogenic	not provided		no assertion criteria provided	clinical testing