ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.1A>G (p.Met1Val) (rs1250300189)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667488 SCV000791945 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2017-05-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000667488 SCV001370577 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2020-05-25 criteria provided, single submitter clinical testing Variant summary: SGSH c.1A>G (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. At the protein level, this alteration results in the replacement of a Methionine residue by Valine in the signal peptide region (Sidhu_2014). Two of two in-silico tools evaluated (Polyphen and BLOSUM 50) predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 91972 control chromosomes. c.1A>G has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Pollard_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000667488 SCV001418486 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-10-24 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SGSH mRNA. The next in-frame methionine is located at codon 88. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. Disruption of the initiator codon has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 22976768, 21204211, 21910976). ClinVar contains an entry for this variant (Variation ID: 552260). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000667488 SCV001440296 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-01-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001531871 SCV001747182 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing

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