Submissions for variant NM_018699.4(PRDM5):c.650+5G>A

gnomAD frequency: 0.00003  dbSNP: rs754469516

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000378562	SCV000447353	uncertain significance	Brittle cornea syndrome 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000482400	SCV000572916	uncertain significance	not provided	2017-02-16	criteria provided, single submitter	clinical testing	The c.650+5G>A variant in the PRDM5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.650+5G>A variant may cause abnormal gene splicing, however, in silico analysis is inconsistent in its predictions as to whether or not the c.650+5G>A variant reduces the quality of the splice donor site in intron 5. The c.650+5G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.650+5G>A as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000482400	SCV002973898	uncertain significance	not provided	2022-02-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the PRDM5 gene. It does not directly change the encoded amino acid sequence of the PRDM5 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs754469516, gnomAD 0.02%). 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: 347447). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.