Submissions for variant NM_052844.4(DYNC2I2):c.1312_1313del (p.Leu438fs)

dbSNP: rs753802842

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824376	SCV000965272	pathogenic	Short-rib thoracic dysplasia 11 with or without polydactyly	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu438Valfs*21) in the WDR34 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the WDR34 protein. This variant is present in population databases (rs753802842, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with WDR34-related conditions. ClinVar contains an entry for this variant (Variation ID: 665979). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the WDR34 protein in which other variant(s) (p.Thr514Argfs*11, p.Thr473Serfs*9, p.Gln494*) have been determined to be pathogenic (PMID: 24183451, 29068549). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000824376	SCV002808770	likely pathogenic	Short-rib thoracic dysplasia 11 with or without polydactyly	2022-05-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000824376	SCV003928778	likely pathogenic	Short-rib thoracic dysplasia 11 with or without polydactyly	2023-02-02	criteria provided, single submitter	clinical testing	Variant summary: DYNC2I2 (WDR34) c.1312_1313delCT (p.Leu438ValfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 251088 control chromosomes. To our knowledge, no occurrence of c.1312_1313delCT in individuals affected with Short-Rib Thoracic Dysplasia 11 With Or Without Polydactyly and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.