Submissions for variant NM_016239.4(MYO15A):c.8080C>A (p.Arg2694Ser)

gnomAD frequency: 0.00006  dbSNP: rs371730430

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001977995	SCV002265252	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 2694 of the MYO15A protein (p.Arg2694Ser). This variant is present in population databases (rs371730430, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 36633841). ClinVar contains an entry for this variant (Variation ID: 1476534). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO15A protein function. 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.
King Laboratory, University of Washington	RCV003155451	SCV003844164	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2023-02-28	criteria provided, single submitter	research	This variant occurred in compound heterozygosity with a MYO15A nonsense variant in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient’s family has no other history of hearing loss. This variant is a missense at a completely conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported to ClinVar as a variant of unknown significance and is not found on gnomAD. Based on consistently predicted functional effect, compound heterozygosity with a loss-of-function variant, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.
Laboratory of Human Genetics, Universidade de São Paulo	RCV004719046	SCV005324777	likely pathogenic	Hearing loss, autosomal recessive	2024-05-01	criteria provided, single submitter	research	The MYO15 NM_016239.3 :c.8080C>A variant has Extremely low frequency in gnomAD population databases, it is associated with a recessive disorder, detected in trans with a pathogenic variant, in compound heterozygous state in affected cases (PM3); computational prediction tools unanimously support a deleterious effect on the gene (PP3). In this report it was found in trans with c.4252G>A, in two affected siblings born from unrelated couple.