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

gnomAD frequency: 0.00001  dbSNP: rs1250300189

Total submissions: 7

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	pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-04-08	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.1A>G (p.Met1?, aka p.Met1Val) 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. Two of two in-silico tools 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 (gnomAD). c.1A>G has been reported in the literature in at least two compound heterozygous individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Pollard_2013, Klau_2022). In addition, other variants affecting the initiation codon (c.1A>C, c.2T>C) have also been reported in affected individuals (HGMD). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (mostly without evidence for independent evaluation), and classified the variant as pathogenic (n=3) / likely pathogenic (n=2), or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000667488	SCV001418486	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-10-30	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 poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with mucopolysaccharidosis type IIIA (PMID: 21204211, 21910976, 22976768). ClinVar contains an entry for this variant (Variation ID: 552260). 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 Center for Human Genetics Tuebingen	RCV001531871	SCV001747182	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	SGSH: PM2, PM3, PP4:Moderate, PS1:Moderate, PVS1:Moderate
Genome-Nilou Lab	RCV000667488	SCV002045112	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001531871	SCV002010072	uncertain significance	not provided	2021-11-03	flagged submission	clinical testing