ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.1A>C (p.Met1Leu)

dbSNP: rs1250300189
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology RCV000856818 SCV000999191 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-07-25 criteria provided, single submitter clinical testing The c.1A>C variant has not been reported as a normal variation in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP and the region was conserved. The variant is also not present in our in-house exome database. This variant is reported in another patient with Sanfilippo A disease (Heron et al. Am J Med Genet A 2011) in Human Genome Mutation Database (CM114840). The variant has been classified as pathogenic according to ACMG guidelines.
Labcorp Genetics (formerly Invitae), Labcorp RCV000856818 SCV002175571 pathogenic Mucopolysaccharidosis, MPS-III-A 2021-09-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SGSH protein in which other variant(s) (p.Arg74) have been determined to be pathogenic (PMID: 9285796, 9401012, 11343308, 28844463). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 Sanfilippo syndrome A (PMID: 21204211, 21910976, 22976768). ClinVar contains an entry for this variant (Variation ID: 694732).

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