Submissions for variant NM_000199.5(SGSH):c.1040C>T (p.Ser347Phe)

gnomAD frequency: 0.00002  dbSNP: rs780239925

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672190	SCV000797270	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2018-01-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000672190	SCV002045150	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672190	SCV002259738	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-01-05	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs780239925, gnomAD 0.03%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser347 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 12438493, 21061399), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SGSH protein function. ClinVar contains an entry for this variant (Variation ID: 556217). This variant is also known as c.1052C>T. This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 12438493; Kim B et al. 2015. J. Korean Soc. Inherit Metab Dis. 15:44). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 347 of the SGSH protein (p.Ser347Phe).
Baylor Genetics	RCV000672190	SCV004201115	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-06-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586867	SCV005076220	uncertain significance	not specified	2024-04-15	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.1040C>T (p.Ser347Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246220 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1040C>T has been reported in the literature in at least one compound heterozygous individual affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A). This report does not provide sufficient evidence to provide any conclusions about association of the variant with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 12438493). ClinVar contains an entry for this variant (Variation ID: 556217). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000672190	SCV005653277	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-04-17	criteria provided, single submitter	clinical testing