ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.6439-2A>G (rs397516330)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036235 SCV000059887 pathogenic Rare genetic deafness 2011-07-07 criteria provided, single submitter clinical testing The 6439-2A>G variant in MYO7A has not been reported in the literature nor previ ously identified by our laboratory in any other families. The 6439-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occu rs in the invariant region of the splice consensus sequence. In summary, this va riant meets our criteria to be classified as pathogenic.
Counsyl RCV000664694 SCV000788697 pathogenic Deafness, autosomal recessive 2; Usher syndrome type 1 2017-01-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778156 SCV000914289 likely pathogenic MYO7A-Related Disorders 2019-04-05 criteria provided, single submitter clinical testing The MYO7A c.6439-2A>G occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.6439-2A>G variant has been reported in three studies in which it was identified in a compound heterozygous state in four individuals with Usher syndrome, including in a pair of siblings (Glockle et al. 2014; Kletke et al. 2017; Neuhaus et al. 2017). The variant was also identified in a compound heterozygous state in two-year-old dizygotic twins with congenital severe, non-progressive hearing loss and likely vestibular dysfunction (Mutai et al. 2013). Whether they later developed retinitis pigmentosa was not reported. In these individuals, each of the identified variants was shown to be inherited from an unaffected heterozygous parent, consistent with autosomal recessive inheritance. The c.6439-2A>G variant has not been reported in association with autosomal dominant hearing loss. It was absent from 192 normal hearing control individuals and is reported at a frequency of 0.000067 in the European (Non-Finnish) population of the Genome Aggregation Database. This frequency is based on one allele only in a region of good sequence coverage, suggesting the variant is rare. Functional studies of the c.6439-2A>G variant have not been reported, but it is predicted to result in aberrant splicing. Based on the collective evidence, the c.6439-2A>G variant is classified as likely pathogenic for MYO7A-related disorders.
Invitae RCV001208546 SCV001379940 pathogenic not provided 2019-10-04 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 47 of the MYO7A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with autosomal recessive deafness in a family (PMID: 24164807). ClinVar contains an entry for this variant (Variation ID: 43329). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). For these reasons, this variant has been classified as Pathogenic.

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