Submissions for variant NM_000199.5(SGSH):c.1462G>A (p.Glu488Lys)

gnomAD frequency: 0.00006  dbSNP: rs145645179

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000348151	SCV000407338	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome-Nilou Lab	RCV000348151	SCV002045117	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000348151	SCV003488657	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 488 of the SGSH protein (p.Glu488Lys). This variant is present in population databases (rs145645179, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SGSH-related conditions. ClinVar contains an entry for this variant (Variation ID: 325826). 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 not expected to disrupt SGSH protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002521129	SCV003531962	uncertain significance	Inborn genetic diseases	2021-09-17	criteria provided, single submitter	clinical testing	The c.1462G>A (p.E488K) alteration is located in exon 8 (coding exon 8) of the SGSH gene. This alteration results from a G to A substitution at nucleotide position 1462, causing the glutamic acid (E) at amino acid position 488 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.