ClinVar Miner

Submissions for variant NM_016616.5(NME8):c.1269G>A (p.Met423Ile)

gnomAD frequency: 0.00004  dbSNP: rs761626831
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000645501 SCV000767247 uncertain significance Primary ciliary dyskinesia 6 2024-04-30 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 423 of the NME8 protein (p.Met423Ile). This variant is present in population databases (rs761626831, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with NME8-related conditions. ClinVar contains an entry for this variant (Variation ID: 536825). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NME8 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV002449045 SCV002682727 uncertain significance Primary ciliary dyskinesia 2014-07-17 criteria provided, single submitter clinical testing The p.M423I variant (also known as c.1269G>A), located in coding exon 13 of the TXNDC3 gene, results from a G to A substitution at nucleotide position 1269. The methionine at codon 423 is replaced by isoleucine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence for this variant is limited at this time, its clinical significance remains unclear.

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