ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs397516330
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1 2017-01-05 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV004528180 SCV000914289 likely pathogenic MYO7A-related disorder 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001208546 SCV001379940 pathogenic not provided 2025-01-03 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. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs397516330, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with autosomal recessive deafness (PMID: 24164807). It has also been observed to segregate with disease in related individuals. 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. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001208546 SCV001446975 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV004814953 SCV005072680 pathogenic Retinal dystrophy 2021-01-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005007949 SCV005629491 pathogenic Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1 2024-06-18 criteria provided, single submitter clinical testing
GeneDx RCV001208546 SCV005882136 likely pathogenic not provided 2024-09-01 criteria provided, single submitter clinical testing Observed multiple times with a pathogenic variant in unrelated patients with features of MYO7A-related Usher spectrum disorder in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 27743452); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31964843, 38219857, 23591405, 28944237, 27743452, 37734845, 36669873, 24164807)
Natera, Inc. RCV001275537 SCV001460752 pathogenic Usher syndrome type 1B 2020-09-16 no assertion criteria provided clinical testing

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