Submissions for variant NM_018699.4(PRDM5):c.1513dup (p.Arg505fs)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002292182	SCV002584488	pathogenic	not provided	2022-10-13	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155475	SCV003845051	likely pathogenic	Brittle cornea syndrome 2	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: PRDM5 c.1513dupA (p.Arg505LysfsX10) 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. Truncations downstream of this position have been reported in HGMD in association with Brittle cornea syndrome and Osteogenesis imperfecta. The variant was absent in 250962 control chromosomes. To our knowledge, no occurrence of c.1513dupA in individuals affected with Brittle Cornea Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002292182	SCV004512853	pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg505Lysfs*10) in the PRDM5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRDM5 are known to be pathogenic (PMID: 21664999, 26395458). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PRDM5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1710895). For these reasons, this variant has been classified as Pathogenic.