Submissions for variant NM_000199.5(SGSH):c.1272_1282del (p.Tyr424_Arg428delinsTer)

dbSNP: rs752914124

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000484018	SCV000340680	pathogenic	not provided	2016-03-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000484018	SCV000568749	pathogenic	not provided	2018-04-20	criteria provided, single submitter	clinical testing	The c.1272_1282del11 variant in the SGSH gene has been reported previously in association with Sanfilippo Syndrome A, also known as MPS IIIA (Scott et al., 1995; Truxal et al., 2016). It is reported as pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000340680.2; Landrum et al., 2016). The c.1272_1282del11 variant causes a frameshift, changing codon Tyrosine 424 to a premature Stop codon, which eliminates the last 79 amino acids from the protein, and is denoted p.Tyr424Ter. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1272_1282del11 variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1272_1282del11 as a pathogenic variant.
Counsyl	RCV000295921	SCV000798140	pathogenic	Mucopolysaccharidosis, MPS-III-A	2018-02-27	criteria provided, single submitter	clinical testing
Invitae	RCV000295921	SCV000955282	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr424*) in the SGSH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the SGSH protein. This variant is present in population databases (rs752914124, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with SGSH-related conditions (PMID: 7493035, 27590925). ClinVar contains an entry for this variant (Variation ID: 287037). This variant disrupts a region of the SGSH protein in which other variant(s) (p.Trp471*) have been determined to be pathogenic (Invitae). 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.
Genome-Nilou Lab	RCV000295921	SCV002045484	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000295921	SCV002051331	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-12-23	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.1272_1282del11 (p.Tyr424X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been classified as pathogenic by our laboratory but have been reported in the HGMD database with a reported phenotype of Sanfillipo syndrome A. The variant allele was found at a frequency of 4e-06 in 250606 control chromosomes. c.1272_1282del11 has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (example, Scott_1997, Weber_1997). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000295921	SCV004201103	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-08-19	criteria provided, single submitter	clinical testing
OMIM	RCV000295921	SCV000025605	pathogenic	Mucopolysaccharidosis, MPS-III-A	1997-05-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003994	SCV001162038	pathogenic	Global developmental delay; Diarrhea; Nystagmus; Retinal dystrophy; Severely reduced visual acuity; Developmental regression; Gastrointestinal dysmotility		no assertion criteria provided	research
Natera, Inc.	RCV000295921	SCV002095113	pathogenic	Mucopolysaccharidosis, MPS-III-A	2020-03-03	no assertion criteria provided	clinical testing