ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.220C>T (p.Arg74Cys) (rs104894636)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078354 SCV000227052 pathogenic not provided 2016-09-02 criteria provided, single submitter clinical testing
GeneDx RCV000078354 SCV000321945 pathogenic not provided 2017-06-15 criteria provided, single submitter clinical testing The R74C variant in the SGSH gene has been reported previously in the homozygous state and in the presence of a second SGSH variant in individuals with mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome type A (Weber et al., 1997; Muschol et al., 2011; Shapiro et al., 2016). The R74C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R74C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and expression studies show that R74C is associated with very low sulfamidase production compared to wild-type (Perkins et al., 1999). Therefore, we interpret R74C as a pathogenic variant.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000005415 SCV000590925 pathogenic Mucopolysaccharidosis, MPS-III-A 2017-06-07 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000005415 SCV000745252 pathogenic Mucopolysaccharidosis, MPS-III-A 2015-09-21 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626628 SCV000747329 likely pathogenic Abnormality of carbohydrate metabolism/homeostasis 2017-01-01 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000005415 SCV000782576 pathogenic Mucopolysaccharidosis, MPS-III-A 2017-01-19 criteria provided, single submitter clinical testing
Invitae RCV000005415 SCV000820679 pathogenic Mucopolysaccharidosis, MPS-III-A 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 74 of the SGSH protein (p.Arg74Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs104894636, ExAC 0.04%). This variant has been reported as homozygous and in combination with other SGSH variants in several individuals  affected with MPS IIIA syndrome and is the most common mutation in Polish patients with MPS IIIA (PMID: 9285796, 28844463, 22976768, 9401012). ClinVar contains an entry for this variant (Variation ID: 5108). Experimental studies have shown that this missense change  leads to defects in enzyme activity and degradation of heparan sulfate (PMID: 10601282, 15146460). A different missense substitution at this codon (p.Arg74His) has been reported in individuals affected with mucopolysaccharidosis type IIIA (PMID: 9401012, 15542396). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000005415 SCV000929892 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2019-01-01 criteria provided, single submitter literature only PS3: Low/absent in vivo enzymatic activity in homozygote. PS3: Low in vitro enzymatic activity. PM2: Very low frequency in GnomAD
OMIM RCV000005415 SCV000025597 pathogenic Mucopolysaccharidosis, MPS-III-A 1997-01-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000005415 SCV000733744 pathogenic Mucopolysaccharidosis, MPS-III-A no assertion criteria provided clinical testing
Counsyl RCV000005415 SCV001132483 pathogenic Mucopolysaccharidosis, MPS-III-A 2016-11-18 no assertion criteria provided clinical testing

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