Submissions for variant NM_000199.5(SGSH):c.1426del (p.His476fs)

dbSNP: rs2041597805

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001942025	SCV002228617	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-08-24	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the SGSH gene (p.His476Thrfs*115). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the SGSH protein and extend the protein by 87 additional amino acid residues. This variant is not present in population databases (ExAC no frequency). This frameshift has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 21204211). This variant disrupts a region of the SGSH protein in which other variant(s) (p.Trp479*) have been determined to be pathogenic (PMID: 21204211). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003365602	SCV004070752	pathogenic	Inborn genetic diseases	2023-07-03	criteria provided, single submitter	clinical testing	The c.1426delC (p.H476Tfs*115) alteration, located in exon 8 (coding exon 8) of the SGSH gene, consists of a deletion of one nucleotide at position 1426, causing a translational frameshift with a predicted alternate stop codon after 115 amino acids. This alteration occurs at the 3' terminus of the SGSH gene, is not expected to trigger nonsense-mediated mRNA decay and results in the elongation of the protein by 87 amino acids. This frameshift impacts the last 27 amino acids of the native protein. However, frameshifts are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in an individual with mucopolysaccharidosis type III in conjunction with a second SGSH frameshift alteration and with low (<10%) enzyme activity (H&eacute;ron, 2011) Based on the available evidence, this alteration is classified as pathogenic.