ClinVar Miner

Submissions for variant NM_006904.7(PRKDC):c.4138G>A (p.Ala1380Thr)

gnomAD frequency: 0.00002  dbSNP: rs56209904
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768057 SCV000898911 uncertain significance Severe combined immunodeficiency due to DNA-PKcs deficiency 2021-03-30 criteria provided, single submitter clinical testing PRKDC NM_006904.6 (LRG_162) exon 33 p.Ala1380Thr (c.4138G>A): This variant has not been reported in the literature but is present in 0.008% (3/34524) of Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/8-48801717-C-T). This variant amino acid Threonine (Thr) is present in 3 species (chinese hamster, golden hamster, tenrec) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV000768057 SCV001384434 uncertain significance Severe combined immunodeficiency due to DNA-PKcs deficiency 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1380 of the PRKDC protein (p.Ala1380Thr). This variant is present in population databases (rs56209904, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. ClinVar contains an entry for this variant (Variation ID: 625999). 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 PRKDC 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.

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