Submissions for variant NM_000199.5(SGSH):c.235A>C (p.Thr79Pro)

dbSNP: rs779703983

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413476	SCV000491272	likely pathogenic	not provided	2016-05-05	criteria provided, single submitter	clinical testing	The T79P variant in the SGSH gene has been reported previously in an individual with Sanfilippo A syndrome. This individual was heterozygous for a second variant that was assumed to be in trans with T79P (Weber et al., 1997). The T79P 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 T79P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R74C, R74H, G80V, H84Y, H84R) have been reported in the Human Gene Mutation Database in association with Sanfilippo syndrome A (Stenson et al., 2014), supporting the functional importance of this region of the protein. The T79P variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035206	SCV001198521	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-04-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 79 of the SGSH protein (p.Thr79Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9285796, 11182930; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372782). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV001035206	SCV002060010	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-11	criteria provided, single submitter	clinical testing	NM_000199.3(SGSH):c.235A>C(T79P) is a missense variant classified as likely pathogenic in the context of mucopolysaccharidosis type IIIA. T79P has been observed in cases with relevant disease (PMID: 22976768, 11182930, 9285796). Functional assessments of this variant are not available in the literature. T79P has not been observed in population frequency databases. In summary, NM_000199.3(SGSH):c.235A>C(T79P) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV001035206	SCV004201104	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-03-18	criteria provided, single submitter	clinical testing