Submissions for variant NM_000199.5(SGSH):c.416C>T (p.Thr139Met)

gnomAD frequency: 0.00001  dbSNP: rs775112689

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001293360	SCV001481815	likely pathogenic	Intellectual disability	2021-02-25	criteria provided, single submitter	clinical testing	The variant chr17-78188504-G-A, SGSH(NM_000199.5):c.416C>T,p.(Thr139Met) was identified in an individual with NDD. Inheritance was not applicable (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Likely Pathogenic (criteria: PM2_Supporting, PM3_Strong, PP3_Supporting, PP4_Supporting). This variant was identified in a compound heterozygous state with the variantNM_000199.5(SGSH):c.267C>A (p.Tyr89Ter) ( Variation ID: 983123).
Genome-Nilou Lab	RCV000666794	SCV002045105	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000666794	SCV002060236	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2021-11-12	criteria provided, single submitter	clinical testing	NM_000199.3(SGSH):c.416C>T(T139M) is a missense variant classified as a variant of uncertain significance in the context of mucopolysaccharidosis type IIIA. T139M has been observed in cases with relevant disease (PMID: 9285796; 24576347). Functional assessments of this variant are not available in the literature. T139M has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000199.3(SGSH):c.416C>T(T139M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000666794	SCV003443328	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2024-05-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 139 of the SGSH protein (p.Thr139Met). This variant is present in population databases (rs775112689, gnomAD 0.004%). This missense change has been observed in individual(s) with Sanfilippo syndrome (PMID: 9285796, 24576347). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551670). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SGSH protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV000666794	SCV004100649	uncertain significance	Mucopolysaccharidosis, MPS-III-A		criteria provided, single submitter	clinical testing	The missense variant p.T139M in SGSH (NM_000199.5) has been submitted previously to ClinVar with conflicting interpretations of pathogenicity (Likely Pathogenic/ Uncertain Significance). No details for independent assesment are available for the Likely Pathogenic classification. It has not been reported previously in affected individuals to the best of our knowledge. The p.T139M variant is observed in 1/16,194 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.T139M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 139 of SGSH is conserved in all mammalian species. The nucleotide c.416 in SGSH is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Baylor Genetics	RCV000666794	SCV004201089	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-02-08	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000666794	SCV005416303	likely pathogenic	Mucopolysaccharidosis, MPS-III-A		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PM3+PP1+PP4
Fulgent Genetics, Fulgent Genetics	RCV000666794	SCV005653290	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-03-07	criteria provided, single submitter	clinical testing
Section for Clinical Neurogenetics, University of Tübingen	RCV000666794	SCV001156105	pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-08-01	no assertion criteria provided	research