ClinVar Miner

Submissions for variant NM_001040716.2(PC):c.1185+5_1185+8del (rs748620956)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489540 SCV000577158 likely pathogenic not provided 2017-04-08 criteria provided, single submitter clinical testing The c.1185+5_1185+8delGCGG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1185+5_1185+8delGCGG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.1185+5_1185+8delGCGG destroys the the natural donor site of intron 10 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. In summary, based on the currently available information, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000489540 SCV000611065 uncertain significance not provided 2017-06-02 criteria provided, single submitter clinical testing
Counsyl RCV000675082 SCV000800586 uncertain significance Pyruvate carboxylase deficiency 2017-09-05 criteria provided, single submitter clinical testing
Invitae RCV000675082 SCV000946964 uncertain significance Pyruvate carboxylase deficiency 2018-07-27 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the PC gene. It does not directly change the encoded amino acid sequence of the PC protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs748620956, ExAC 0.03%). This variant has not been reported in the literature in individuals with PC-related disease. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.

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