Submissions for variant NM_000199.5(SGSH):c.697C>T (p.Arg233Ter)

gnomAD frequency: 0.00003  dbSNP: rs374621913

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409562	SCV000486121	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2016-11-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588098	SCV000695959	pathogenic	Sanfilippo syndrome	2017-07-17	criteria provided, single submitter	clinical testing	Variant summary: The c.697C>T (p.Arg233*) variant in SGSH gene is a nonsense change that results in the loss of the ~54% of the length of the protein (270 aa). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay, which was proven by RNA and protein expression studies (Muschol, 2004). The variant is present in the large control population dataset of ExAC at a low frequency 1.1e-05 (1/90902 chrs tested). This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.0032 in this gene. The variant of interest has been reported in numerous affected individual homozygously or in compound heterozygous state. In addition, the variant is cited as Pathogenic by multiple reputable database/diagnostic centers. Taking together, the variant was classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000409562	SCV000893482	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409562	SCV000937104	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg233*) in the SGSH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGSH are known to be pathogenic (PMID: 11182930, 21204211, 22976768). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 15146460). ClinVar contains an entry for this variant (Variation ID: 370732). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000409562	SCV002045497	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV003128796	SCV003805365	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, Natalia2015[Abstract], 34047372, 11182930, 15146460)
Baylor Genetics	RCV000409562	SCV004201101	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-03-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004022138	SCV004948762	pathogenic	Inborn genetic diseases	2023-12-29	criteria provided, single submitter	clinical testing	The c.697C>T (p.R233*) alteration, located in exon 6 (coding exon 6) of the SGSH gene, consists of a C to T substitution at nucleotide position 697. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 233. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (4/268038) total alleles studied. The highest observed frequency was 0.006% (2/34596) of Latino alleles. This alteration was detected, in conjunction with another alteration in SGSH, in multiple individuals with Mucopolysaccharidosis type IIIA (Beesley, 2000; Ghosh, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000409562	SCV005374124	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-09-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000409562	SCV001453821	pathogenic	Mucopolysaccharidosis, MPS-III-A	2020-09-16	no assertion criteria provided	clinical testing