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

gnomAD frequency: 0.00001  dbSNP: rs121912559

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154352	SCV000204015	uncertain significance	not specified	2014-04-28	criteria provided, single submitter	clinical testing	The Glu216Val variant in MYO6 has been reported in homozygous state in one Pakis tani individual with severe-to-profound hearing loss and was not identified in 5 40 ethnically matched chromosomes (Ahmed 2003). Although this information sugges ts a role for this variant, it is possible that the variant segregates with anot her 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 v ariant 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