ClinVar Miner

Submissions for variant NM_001289104.2(PRKCSH):c.1009G>A (p.Val337Met)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002914783 SCV003268300 uncertain significance not provided 2023-07-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the PRKCSH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PRKCSH are known to be pathogenic (PMID: 12529853, 12577059, 20095989). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 2057120). This variant has not been reported in the literature in individuals affected with PRKCSH-related conditions. This variant is present in population databases (rs373416744, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant.
Ambry Genetics RCV004067120 SCV005011678 uncertain significance Inborn genetic diseases 2023-10-17 criteria provided, single submitter clinical testing The c.1008+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 10 of the PRKCSH gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.013% (31/238808) total alleles studied. The highest observed frequency was 0.136% (23/16890) of East Asian alleles. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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