Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001325860 | SCV001516869 | likely pathogenic | not provided | 2023-04-09 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1170 of the MYO7A protein (p.Glu1170Gly). 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 disrupts the p.Glu1170 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10425080, 15043528, 21436283). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. ClinVar contains an entry for this variant (Variation ID: 1025532). This missense change has been observed in individual(s) with MYO7A-related conditions (PMID: 36633841). This variant is present in population databases (no rsID available, gnomAD 0.003%). |
King Laboratory, |
RCV003155394 | SCV003844137 | likely pathogenic | Usher syndrome type 1 | 2023-02-28 | criteria provided, single submitter | research | This variant occurred in compound heterozygosity with a MYO7A missense variant in a patient with Usher syndrome including 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 in a MyTH4 domain of the MYO7A protein and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported to ClinVar as likely pathogenic and is found in 1 heterozygote on gnomAD. Based on consistently predicted functional effect and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. |
Prevention |
RCV004528466 | SCV004109903 | uncertain significance | MYO7A-related disorder | 2023-01-04 | criteria provided, single submitter | clinical testing | The MYO7A c.3509A>G variant is predicted to result in the amino acid substitution p.Glu1170Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-76900394-A-G). A different pathogenic amino acid substitution affecting this residue (p.Glu1170Lys) has been reported in multiple patients with Usher syndrome type 1 (Cuevas et al. 1999. PubMed ID: 10425080; Nájera et al 2002. PubMed ID: 12112664; Table S1, Bonnet et al. 2016. PubMed ID: 27460420, Roux et al. 2011. PubMed ID: 21436283). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV004587122 | SCV005076367 | uncertain significance | not specified | 2024-10-14 | criteria provided, single submitter | clinical testing | Variant summary: MYO7A c.3509A>G (p.Glu1170Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248640 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3509A>G has been reported in the literature in an individual affected with bilateral sensorineural hearing loss, with no second allele specified (Carlson_2023). This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 36633841). ClinVar contains an entry for this variant (Variation ID: 1025532). Based on the evidence outlined above, the variant was classified as uncertain significance. |
Natera, |
RCV001831011 | SCV002086672 | uncertain significance | Usher syndrome type 1B | 2020-12-07 | no assertion criteria provided | clinical testing |