Submissions for variant NM_000199.5(SGSH):c.1027dup (p.Leu343fs)

dbSNP: rs778700037

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000478433	SCV000232479	pathogenic	not provided	2014-06-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000478433	SCV000568750	likely pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	Reported previously in association with mucopolysaccharidosis IIIA (MPS IIIA); however it is unclear if a second SGSH variant was identified (Weber et al., 1997; Pollard et al., 2013); Frameshift variant predicted to result in protein truncation, as the last 160 amino acids are replaced with 158 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22976768, 15146460, 9285796, 24314109, 21204211)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586132	SCV000695955	pathogenic	Sanfilippo syndrome	2017-02-02	criteria provided, single submitter	clinical testing	Variant summary: The SGSH c.1027dupC (p.Leu343Profs) variant results in a premature termination codon, predicted to cause a truncated or absent SGSH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 7/118674 control chromosomes at a frequency of 0.000059, which does not exceed the estimated maximal expected allele frequency of a pathogenic SGSH variant (0.0032275). This variant has been reported in multiple affected individuals as compund heterozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000180105	SCV001233391	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu343Profs*159) in the SGSH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 160 amino acid(s) of the SGSH protein. This variant is present in population databases (rs778700037, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 15146460, 21204211, 24314109). This variant is also known as c.1026dupC, c.1027_1028insC, and insC1039. ClinVar contains an entry for this variant (Variation ID: 198694). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SGSH function (PMID: 15146460). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266816	SCV001444995	pathogenic	Inborn genetic diseases	2019-12-26	criteria provided, single submitter	clinical testing	The alteration results in a premature stop codon: The c.1027dupC (p.L343Pfs*159) alteration, located in coding exon 8 of the SGSH gene, consists of a duplication of C at position 1027, causing a translational frameshift with a predicted alternate stop codon after 159 amino acids. Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of SGSH, is not expected to trigger nonsense-mediated mRNA decay, and a truncated mutant protein could still be expressed (Maquat, 2004). This alteration impacts the last 160 amino acids of the protein and the exact functional impact of these altered amino acids is unknown at this time; however, this alteration and additional truncating alterations downstream of this alteration have been reported in the literature as disease-causing. The alteration is rare in population databases: Based on data from the Genome Aggregation Database (gnomAD), the c.1027dupC alteration was observed in 0.0036% (10/276396) of total alleles studied, with a frequency of 0.0070% (9/127824) in the European (non-Finnish) subpopulation. This alteration has been observed in affected individuals: This alteration has been reported in cohorts of patients with MPS type III, although the specific genotype and phenotype of affected patients were not available (Pollard, 2013; Weber, 1997). This alteration has also been reported as C1039 in the literature. Based on the available evidence, this alteration is classified as pathogenic.
Genome-Nilou Lab	RCV000180105	SCV002045491	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000180105	SCV002813323	pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-04-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000180105	SCV004201083	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-10-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000180105	SCV000486596	pathogenic	Mucopolysaccharidosis, MPS-III-A	2016-11-03	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000180105	SCV001463875	pathogenic	Mucopolysaccharidosis, MPS-III-A	2020-09-16	no assertion criteria provided	clinical testing