ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.1080del (p.Val361fs) (rs770947426)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000606285 SCV000745247 pathogenic Mucopolysaccharidosis, MPS-III-A 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000606285 SCV000733739 pathogenic Mucopolysaccharidosis, MPS-III-A no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000606285 SCV000920205 pathogenic Mucopolysaccharidosis, MPS-III-A 2018-09-14 criteria provided, single submitter clinical testing Variant summary: SGSH c.1080delC (p.Val361SerfsX52) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.5e-05 in 275896 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in SGSH causing Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (6.5e-05 vs 0.0032), allowing no conclusion about variant significance. The variant, c.1080delC, has been reported in the literature in multiple individuals (inlcuding homozygotes) affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A), being one of the most frequent variants associated with the disease (Montfort 2004, Heron 2010). At least two publications reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Montfort 2004, Heron 2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000606285 SCV000754683 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-01-06 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SGSH gene (p.Val361Serfs*52). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 142 amino acids of the SGSH protein. This variant is present in population databases (rs770947426, ExAC 0.009%). This variant has been reported as homozygous or in combination with another SGSH variant in individuals affected with mucopolysaccharidosis type III (PMID: 15542396, 21910976, 22976768, 21061399, 9285796). This variant is also known as c.1091delC and delC1091 in the literature. ClinVar contains an entry for this variant (Variation ID: 518268). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000606285 SCV000929900 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-01-01 criteria provided, single submitter literature only PVS1: frameshift. PS3: Low in vitro enzymatic acitivity. PM2: Absent from GnomAD

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