ClinVar Miner

Submissions for variant NM_001366110.1(PAX4):c.1013C>T (p.Ala338Val)

gnomAD frequency: 0.00062  dbSNP: rs2233583
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002034958 SCV002111166 uncertain significance not provided 2025-01-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 330 of the PAX4 protein (p.Ala330Val). This variant is present in population databases (rs2233583, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PAX4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1345146). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
New York Genome Center RCV002468339 SCV002764271 uncertain significance Maturity-onset diabetes of the young type 9; Type 2 diabetes mellitus 2021-04-09 criteria provided, single submitter clinical testing The heterozygous c.1013C>T (p.Ala338Val) variant identified in the PAX4 gene substitutes a moderately conserved Alanine for Valine at amino acid 338/352 (exon 12/12). This variant is identified in 81 heterozygotes and 1 homozygote in gnomAD(v3.1.1) withan allele frequency of 5.32e-4 . In silico algorithms do not agree on the effect of this variant, as it is predicted both Deleterious (SIFT; score:0.003) and Benign (REVEL; score:0.227) to the functionof the canonicaltranscript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, the heterozygous c.1013C>T (p.Ala338Val) variant identified in the PAX4 gene is reported as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV002034958 SCV004562203 likely benign not provided 2023-09-06 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV002034958 SCV005195629 uncertain significance not provided criteria provided, single submitter not provided

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