ClinVar Miner

Submissions for variant NM_016239.4(MYO15A):c.9913G>A (p.Glu3305Lys)

gnomAD frequency: 0.00003  dbSNP: rs535441567
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523960 SCV000620352 uncertain significance not provided 2017-09-12 criteria provided, single submitter clinical testing The E3305K variant in the MYO15A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E3305K variant is observed in 14/16512 (0.085%) alleles from individuals of South Asian background in large population cohorts, with no homozygotes observed (Lek et al., 2016). The E3305K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret E3305K as a variant of uncertain significance.
Invitae RCV000523960 SCV001599768 likely benign not provided 2024-01-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000523960 SCV001550556 uncertain significance not provided no assertion criteria provided clinical testing The MYO15A p.E3305K variant was not identified in the literature but was identified in dbSNP (ID: rs535441567) and ClinVar (classified as uncertain significance by GeneDx). The variant was identified in control databases in 35 of 280690 chromosomes (1 homozygous) at a frequency of 0.0001247, and was observed at the highest frequency in the South Asian population in 23 of 30602 chromosomes (freq: 0.0007516) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.E3305 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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