ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.734G>A (p.Arg245His) (rs104894635)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623663 SCV000741895 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000078356 SCV000610021 pathogenic not provided 2017-05-24 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000005414 SCV000745249 pathogenic Mucopolysaccharidosis, MPS-III-A 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000005414 SCV000733741 pathogenic Mucopolysaccharidosis, MPS-III-A no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078356 SCV000231496 pathogenic not provided 2015-10-01 criteria provided, single submitter clinical testing
GeneDx RCV000078356 SCV000321946 pathogenic not provided 2017-11-02 criteria provided, single submitter clinical testing The R245H pathogenic variant in the SGSH gene has been reported previously in association with mucopolysaccharidosis IIIA (MPS IIIA) (Weber et al., 1997; Blanch et al., 1997; Lee-Chen et al., 2002; Wilkin et al., 2015). The R245H variant is a common pathogenic variant in Australian, Dutch and German patients; in one study of 109 patients with MPS IIIA, the R245H pathogenic variant accounted for 31% of disease causing alleles in Australasia, and 57.8% of disease causing alleles in The Netherlands (Weber et al., 1997). This variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While the R245H variant is a conservative amino acid substitution, this substitution occurs at a position that is conserved across species, and functional analysis of R245H demonstrates that it is associated with significantly reduced enzyme activity and rapid protein degradation (Perkins et al., 1999). We interpret R245H as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000005414 SCV000407358 pathogenic Mucopolysaccharidosis, MPS-III-A 2017-04-27 criteria provided, single submitter clinical testing The SGSH c.734G>A (p.Arg245His) variant is one of the most commonly detected variants in individuals with mucopolysaccharidosis type III, accounting for up to 58% of disease alleles in some European populations (Fedele et al. 2015). Across a selection of the available literature, the p.Arg245His variant has been identified in a homozygous state in 37 individuals, in a compound heterozygous state in 75 individuals, and in a heterozygous state in two individuals (Blanch et al. 1997; Weber et al. 1998; Meyer et al. 2008; Valstar et al. 2010; Wilkin et al. 2016). The variant was absent from 20 control alleles but is reported at a frequency of 0.00060 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Arg245 residue is not conserved among human sulphatases. Functional studies showed that the p.Arg245His variant protein is expressed at a lower level than wild type, affects protein stability, and results in 83% of normal activity (Perkins et al. 1999; Sidhu et al. 2014). Based on the collective evidence, the p.Arg245His variant is classified as pathogenic for mucopolysaccharidosis type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000348775 SCV000695960 pathogenic Sanfilippo syndrome 2016-06-26 criteria provided, single submitter clinical testing Variant summary: The SGSH c.734G>A (p.Arg245His) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 30/72670 (1/2422), which does not exceed the estimated maximal expected allele frequency for a pathogenic SGSH variant of 1/309. The variant of interest has been reported in multiple affected individuals as homozygotes and compound heterozygotes via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Invitae RCV000005414 SCV000833727 pathogenic Mucopolysaccharidosis, MPS-III-A 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 245 of the SGSH protein (p.Arg245His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs104894635, ExAC 0.06%). This variant has been reported as homozygous or in combination with another SGSH variant in multiple individuals affected with mucopolysaccharidosis type IIIA (PMID: 9158154, 9700599, 15146460, 22976768, 21061399) and in one individual affected with this condition in whom this variant has been observed on the opposite chromosome (in trans) from another likely pathogenic variant (PMID: 26331342). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 5107). Experimental studies have shown that this missense change abrogates SGSH enzyme activity (PMID: 10601282). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000005414 SCV000929899 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-01-01 criteria provided, single submitter literature only PS3: Low/absent in vivo enzymatic activity in homozygote; Low in vitro enzymatic activity. PS4: The prevalence of the variant in affected individuals is significantly increase compared with the prevalence in controls. PM2: Absent from GnomAD
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000078356 SCV000801902 pathogenic not provided 2017-04-19 no assertion criteria provided clinical testing
OMIM RCV000005414 SCV000025596 pathogenic Mucopolysaccharidosis, MPS-III-A 1998-06-01 no assertion criteria provided literature only

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