ClinVar Miner

Submissions for variant NM_001029883.3(PCARE):c.920T>A (p.Leu307Ter)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001355875 SCV001588456 pathogenic not provided 2020-09-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu307*) in the PCARE gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with retinitis pigmentosa (PMID: 28763557). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in PCARE are known to be pathogenic (PMID: 20398886, 24339724, 26496393). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355875 SCV001550888 likely pathogenic not provided no assertion criteria provided clinical testing The PCARE p.307* variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs1397537890) and in control databases in 1 of 249396 chromosomes at a frequency of 0.00000401 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 1 of 113222 chromosomes (freq: 0.000009), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.920T>A variant leads to a premature stop codon at position 307 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PCARE gene are an established mechanism of disease in autosomal recessive retinitis pigmentosa and is the type of variant expected to cause the disorder when found in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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