Submissions for variant NM_006904.6(PRKDC):c.6901C>G (p.Gln2301Glu) (rs376211703)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000652364	SCV000774234	uncertain significance	Immunodeficiency 26 with or without neurologic abnormalities	2019-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with glutamic acid at codon 2301 of the PRKDC protein (p.Gln2301Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs376211703, ExAC 0.09%). This variant has not been reported in the literature in individuals with PRKDC-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000652364	SCV000898909	uncertain significance	Immunodeficiency 26 with or without neurologic abnormalities	2018-03-01	criteria provided, single submitter	clinical testing	PRKDC NM_006904.6 exon 52 p.Gln2301Glu (c.6901C>G): This variant has not been reported in the literature but is present in 63/85696 European alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs376211703). This variant Glutamic Acid (Glu) is present in >15 species 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.

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