Submissions for variant NM_006904.7(PRKDC):c.10172C>T (p.Ala3391Val)

gnomAD frequency: 0.00008  dbSNP: rs562934408

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001225199	SCV001397440	uncertain significance	Severe combined immunodeficiency due to DNA-PKcs deficiency	2022-05-05	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 3391 of the PRKDC protein (p.Ala3391Val). This variant is present in population databases (rs562934408, gnomAD 0.03%). 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: 952977). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001225199	SCV002769352	uncertain significance	Severe combined immunodeficiency due to DNA-PKcs deficiency	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_006904.6(PRKDC):c.10172C>T, has been identified in exon 72 of 86 of the PRKDC gene. The variant is predicted to result in a minor amino acid change from an alanine to a valine at position 3391 of the protein, NP_008835.5(PRKDC):p.(Ala3391Val). The alanine residue at this position has low conservation (100 vertebrates, UCSC), and is located within the FAT domain. In silico predictions for this variant are consistently benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.02% (42 heterozygotes, 0 homozygotes). This variant has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.