ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.3750+5G>A (rs111033391)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036124 SCV000059776 uncertain significance not specified 2017-08-17 criteria provided, single submitter clinical testing The c.3750+5G>A variant in MYO7A has now been identified by our laboratory in 4 individuals with hearing loss, 2 of those also have retinal abnormalities. Howev er, a second variant in MYO7A was not found in any of them. This variant has bee n identified in 0.1% (93/76532) of European chromosomes and 0.07% (125/185496) o f total chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs111033391). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. This variant is located in the 5' splice region. Computational tools sugges t a possible impact to splicing. However, this information is not predictive eno ugh to determine pathogenicity. In summary, the clinical significance of the c.3 750+5G>A variant is uncertain.
GeneDx RCV000728067 SCV000618049 uncertain significance not provided 2018-10-25 criteria provided, single submitter clinical testing The c.3750+5 G>A variant in the MYO7A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to reduce the quality of the splice donor site in intron 29, and is expected to cause abnormal gene splicing. The c.3750+5 G>A variant is observed in 125/185496 (0.0674%) alleles in large population cohorts (Lek et al., 2016). We interpret c.3750+5G>A as a variant of uncertain significance.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000660456 SCV000782549 uncertain significance Deafness, autosomal dominant 11; Deafness, autosomal recessive 2; Usher syndrome type 1 2016-12-15 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000728067 SCV000855593 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing
Invitae RCV000728067 SCV001417585 uncertain significance not provided 2019-10-21 criteria provided, single submitter clinical testing This sequence change falls in intron 29 of the MYO7A gene. It does not directly change the encoded amino acid sequence of the MYO7A protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs111033391, ExAC 0.4%). This variant has not been reported in the literature in individuals with MYO7A-related disease. ClinVar contains an entry for this variant (Variation ID: 43220). 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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