ClinVar Miner

Submissions for variant NM_014254.3(RXYLT1):c.914+6T>G (rs748809209)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492906 SCV000582515 uncertain significance not provided 2017-05-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TMEM5 gene. The c.914+6 T>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.914+6 T>G variant 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.914+6 T>G reduces the natural splice donor site and may 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000698558 SCV000827228 uncertain significance Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 2018-05-16 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the TMEM5 gene. It does not directly change the encoded amino acid sequence of the TMEM5 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs748809209, ExAC 0.002%). This variant has not been reported in the literature in individuals with TMEM5-related disease. ClinVar contains an entry for this variant (Variation ID: 429848). 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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