Submissions for variant NM_000199.5(SGSH):c.1322G>A (p.Arg441Gln)

gnomAD frequency: 0.00096  dbSNP: rs142599919

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001127067	SCV001286338	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553765	SCV001774759	uncertain significance	not specified	2021-07-15	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.1322G>A (p.Arg441Gln) results in a conservative amino acid change located in the Domain of unknown function DUF4976 (IPR032506) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0009 in 250012 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in SGSH causing Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (0.0009 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1322G>A in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV001127067	SCV002045128	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001127067	SCV002548897	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2021-08-25	criteria provided, single submitter	clinical testing
Invitae	RCV001127067	SCV003265792	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 441 of the SGSH protein (p.Arg441Gln). This variant is present in population databases (rs142599919, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 891642). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Natera, Inc.	RCV001127067	SCV002095110	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2020-01-07	no assertion criteria provided	clinical testing