Submissions for variant NM_016239.4(MYO15A):c.8714-1G>A

gnomAD frequency: 0.00006  dbSNP: rs377015931

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155197	SCV000204883	pathogenic	Rare genetic deafness	2014-07-22	criteria provided, single submitter	clinical testing	The 8714-1G>A variant in MYO15A had not been reported in individuals with hearin g loss, but has been identified in 1/4068 of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although t his variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, th is variant meets our criteria to be classified as pathogenic (www.partners.org/p ersonalizedmedicine/lmm).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514987	SCV003305511	likely pathogenic	not provided	2023-08-19	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 49 of the MYO15A 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 MYO15A are known to be pathogenic (PMID: 17546645). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is present in population databases (rs377015931, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. ClinVar contains an entry for this variant (Variation ID: 178449).
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477929	SCV000536882	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2016-03-07	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004745219	SCV005346484	likely pathogenic	MYO15A-related disorder	2024-08-21	no assertion criteria provided	clinical testing	The MYO15A c.8714-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice acceptor site in MYO15A are expected to be pathogenic. This variant is interpreted as likely pathogenic.