ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.235A>C (p.Thr79Pro) (rs779703983)

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Total submissions: 2
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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.
Invitae RCV001035206 SCV001198521 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 79 of the SGSH protein (p.Thr79Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals with mucopolysaccharidosis type III (PMID: 11182930, 9285796, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372782). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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