ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.1272_1282del (p.Tyr424_Arg428delinsTer) (rs752914124)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000484018 SCV000340680 pathogenic not provided 2016-03-25 criteria provided, single submitter clinical testing
GeneDx RCV000484018 SCV000568749 pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing The c.1272_1282del11 variant in the SGSH gene has been reported previously in association with Sanfilippo Syndrome A, also known as MPS IIIA (Scott et al., 1995; Truxal et al., 2016). It is reported as pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000340680.2; Landrum et al., 2016). The c.1272_1282del11 variant causes a frameshift, changing codon Tyrosine 424 to a premature Stop codon, which eliminates the last 79 amino acids from the protein, and is denoted p.Tyr424Ter. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1272_1282del11 variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1272_1282del11 as a pathogenic variant.
Counsyl RCV000295921 SCV000798140 pathogenic Mucopolysaccharidosis, MPS-III-A 2018-02-27 criteria provided, single submitter clinical testing
Invitae RCV000295921 SCV000955282 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr424*) in the SGSH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the SGSH protein. This variant is present in population databases (rs752914124, ExAC 0.003%). This variant has been observed in individuals affected with SGSH-related conditions (PMID: 7493035, 27590925). ClinVar contains an entry for this variant (Variation ID: 287037). This variant disrupts the C-terminus of the SGSH protein. Other variant(s) that disrupt this region (p.Trp471*) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003994 SCV001162038 pathogenic Global developmental delay; Diarrhea; Nystagmus; Retinal dystrophy; Severe visual impairment; Developmental regression; Gastrointestinal dysmotility no assertion criteria provided research

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