Submissions for variant NM_000260.4(MYO7A):c.285+2T>C

dbSNP: rs782292032

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578756	SCV000681080	likely pathogenic	not provided	2018-09-04	criteria provided, single submitter	clinical testing	The c.285+2 T>C splice site variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant destroys the canonical splice donor site in intron 4. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. In summary, this variant is likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000613318	SCV000713173	pathogenic	Rare genetic deafness	2017-05-21	criteria provided, single submitter	clinical testing	The c.285+2T>C variant in MYO7A has not been previously reported in individuals with hearing loss or Usher syndrome. Data from large population studies is insuf ficient to assess the frequency of this variant. This variant occurs in the inva riant region (+/- 1/2) of the splice consensus sequence and is predicted to caus e altered splicing leading to an abnormal or absent protein. Loss of function of the MYO7A gene is an established disease mechanism in Usher syndrome. In summar y, this variant meets criteria to be classified as pathogenic for autosomal rece ssive hearing loss or Usher syndrome based on predicted impact to the protein.
Mendelics	RCV000988600	SCV001138379	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000578756	SCV001584746	pathogenic	not provided	2022-04-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 489095). This sequence change affects a donor splice site in intron 4 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with autosomal recessive Usher syndrome (PMID: 29490346, 33576794; Invitae).