ClinVar Miner

Submissions for variant NM_002519.3(NPAT):c.2063C>T (p.Thr688Met)

gnomAD frequency: 0.00029  dbSNP: rs199837111
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001818089 SCV002067914 uncertain significance not specified 2021-07-27 criteria provided, single submitter clinical testing DNA sequence analysis of the NPAT gene demonstrated a sequence change, c.2063C>T, in exon 13 that results in an amino acid change, p.Thr688Met. This sequence change does not appear to have been previously described in individuals with NPAT-related disorders and has been described in the gnomAD database with a low population frequency of 0.014% (dbSNP rs199837111). The p.Thr688Met change affects a poorly conserved amino acid residue located in a domain of the NPAT protein that is not known to be functional. The p.Thr688Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr688Met change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp RCV003698878 SCV004458050 uncertain significance not provided 2025-01-29 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 688 of the NPAT protein (p.Thr688Met). This variant is present in population databases (rs199837111, gnomAD 0.07%), 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 NPAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1338718). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The methionine 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.

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