ClinVar Miner

Submissions for variant NM_000262.3(NAGA):c.406G>A (p.Asp136Asn) (rs186173534)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000353858 SCV000439003 uncertain significance Alpha-N-acetylgalactosaminidase deficiency type 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000261413 SCV000439004 uncertain significance Alpha-N-acetylgalactosaminidase deficiency type 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000261413 SCV001028211 benign Alpha-N-acetylgalactosaminidase deficiency type 1 2019-12-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001199905 SCV001370664 uncertain significance not specified 2020-05-11 criteria provided, single submitter clinical testing Variant summary: NAGA c.406G>A (p.Asp136Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 282862 control chromosomes, predominantly at a frequency of 0.014 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 1 homozygote. Since the clinical phenotype associated with alpha-N-acetylgalactosaminidase deficiency varies vastly, from asymptomatic to severe infantile form of the disease, even in individuals with the same genotype (see e.g. PMID: 31468281), this relatively high frequency and a single homozygous occurrence in controls might not exclude the association of this variant with disease. To our knowledge, no occurrence of c.406G>A in individuals affected with Kanzaki Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, until further evidence becomes available, the variant was classified as uncertain significance.

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