ClinVar Miner

Submissions for variant NM_004999.4(MYO6):c.647A>T (p.Glu216Val)

gnomAD frequency: 0.00001  dbSNP: rs121912559
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000767071 SCV000204015 uncertain significance not provided 2022-08-26 criteria provided, single submitter clinical testing The p.Glu216Val variant in MYO6 has been reported in homozygous state in one Pakistani individual with severe-to-profound hearing loss and was not identified in 540 ethnically matched chromosomes (Ahmed 2003). Although this information suggests a role for this variant, it is possible that the variant segregates with another variant that is causative for the hearing loss. Additional evidence, such as screening for this variant in a large ethnically-matched control population and functional studies, is needed to assume pathogenicity. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Glu216Val variant is uncertain.
GeneDx RCV000767071 SCV000568841 uncertain significance not provided 2023-04-14 criteria provided, single submitter clinical testing Observed in homozygous state in a patient with congenital sensorineural hearing loss in the literature (Ahmed et al., 2003), however, this individual was not screened for variants in other genes associated with hearing loss, and the variant was also observed in at least one homozygous individual in large population cohorts (gnomAD); Published functional studies are inconclusive regarding the functional impact of this variant (Oka et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31250571, 29224747, 30245029, 32143290, 12687499)
Illumina Laboratory Services, Illumina RCV000009111 SCV000916164 uncertain significance Autosomal recessive nonsyndromic hearing loss 37 2016-10-27 criteria provided, single submitter clinical testing The MYO6 c.647A>T (p.Glu216Val) missense variant has been reported in at least one study in a homozygous state in one individual with hearing loss and in a heterozygous state in at least one unaffected family member (Ahmed et al. 2003). The p.Glu216Val variant was absent from 351 controls, but is reported at a frequency of 0.03398 in the Gujarati Indian in Houston, Texas population from the 1000 Genomes Project. This allele frequency is high but is consistent with the disease prevalence. Computational analyses of the p.Glu216Val variant by Butt et al. (2012) showed that the variant may affect protein stability and result in structural abnormalities that could affect binding properties. The evidence for this variant is limited. The p.Glu216Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics RCV000987740 SCV001137180 uncertain significance Autosomal dominant nonsyndromic hearing loss 22 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000767071 SCV003004083 uncertain significance not provided 2020-07-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with valine at codon 216 of the MYO6 protein (p.Glu216Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is present in population databases (rs121912559, ExAC 0.3%). This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 12687499). ClinVar contains an entry for this variant (Variation ID: 8580). This variant has been reported to affect MYO6 protein function (PMID: 32143290). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
OMIM RCV000009111 SCV000029328 pathogenic Autosomal recessive nonsyndromic hearing loss 37 2003-05-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.