ClinVar Miner

Submissions for variant NM_000262.3(NAGA):c.973G>A (p.Glu325Lys) (rs121434529)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256069 SCV000321922 pathogenic not provided 2017-03-29 criteria provided, single submitter clinical testing The E325K variant in the NAGA gene has been reported previously in both the homozygous andcompound heterozygous states in individuals with alpha-NAGA deficiency (Wang et al., 1990;Keulemans et al., 1996; Bakker et al., 2001). Functional studies indicate that E325K results in loss ofalpha-N-acetylgalactosaminidase activity (Wang et al., 1990). The E325K variant is observed in247/66370 (0.37%) alleles from individuals of European background in the ExAC dataset (Lek et al.,2016). The E325K variant is a non-conservative amino acid substitution, which occurs at a positionwhere amino acids with similar properties to Glutamic Acid are tolerated across species. We interpretE325K as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000256069 SCV000331365 pathogenic not provided 2016-08-16 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000501877 SCV000595898 pathogenic Alpha-N-acetylgalactosaminidase deficiency 2016-03-25 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000019792 SCV000746490 pathogenic Schindler disease, type 1 2017-12-03 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000660647 SCV000782773 pathogenic Kanzaki disease; Schindler disease, type 1 2018-02-16 criteria provided, single submitter clinical testing
Invitae RCV000019792 SCV000825839 pathogenic Schindler disease, type 1 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 325 of the NAGA protein (p.Glu325Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs121434529, ExAC 0.4%). This variant has been reported segregate with alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency in multiple families (PMID: 1131374, 8040340, 7707696, 8071745). Importantly, the clinical presentation associated with alpha-NAGA deficiency varies considerably from asymptomatic to severe infantile neuroaxonal dystrophy (Schindler disease). Multiple experimental studies have demonstrated that this missense change results in nearly complete loss of alpha-NAGA enzyme activity (PMID: 2243144, 8782044, 11313741). In summary, this missense variant has been demonstrated to segregate with alpha-NAGA deficiency. For this reason, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000660647 SCV000893593 likely pathogenic Kanzaki disease; Schindler disease, type 1 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000019792 SCV000040090 pathogenic Schindler disease, type 1 2001-02-01 no assertion criteria provided literature only

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