Submissions for variant NM_000260.4(MYO7A):c.689C>T (p.Ala230Val)

dbSNP: rs797044512

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155771	SCV000205482	pathogenic	Rare genetic deafness	2013-06-11	criteria provided, single submitter	clinical testing	The Ala230Val variant in MYO7A has been reported in a large Italian pedigree aff ected with nonsyndromic post-lingual progressive hearing loss showing autosomal dominant inheritance(Di Leva 2006). The variant co-segregated with hearing loss in several affected family members, and was not identified in unaffected family members or in 200 ethnically matched control chromosomes (Di Leva 2006). In addi tion, this variant was not identified in large population studies. Furthermore, the alanine (Ala) residue at position 230 is located in the conserved motor doma in of the MYO7A protein. Missense variants in this region of the protein have be en associated with autosomal dominant hearing loss. In summary, this variant mee ts our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) b ased upon segregation analysis.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506187	SCV000604428	likely pathogenic	not specified	2016-10-12	criteria provided, single submitter	clinical testing
Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo	RCV001254945	SCV001762978	pathogenic	Bilateral sensorineural hearing impairment		criteria provided, single submitter	research	pathogenic missense heterozygous variant was found to segregate with HL in six members of the same family
Invitae	RCV001850134	SCV002239418	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 230 of the MYO7A protein (p.Ala230Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 16449806, 28802369). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178993). 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 MYO7A protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001850134	SCV002521962	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); 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: 28802369, 16449806)
PreventionGenetics, part of Exact Sciences	RCV003398811	SCV004105633	likely pathogenic	MYO7A-related condition	2023-07-05	criteria provided, single submitter	clinical testing	The MYO7A c.689C>T variant is predicted to result in the amino acid substitution p.Ala230Val. This variant was reported to segregate with disease in a large family with autosomal dominant non-syndromic sensorineural hearing loss (Di Leva et al. 2006. PubMed ID: 16449806). This variant was also reported as de novo in an individual with moderate bilateral hearing loss (Kaneko et al. 2017. PubMed ID: 28802369). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000225087	SCV000281977	pathogenic	Autosomal dominant nonsyndromic hearing loss 11	2016-02-16	no assertion criteria provided	research	childhood onset, progressive HL, also myopia
New York Genome Center	RCV001254945	SCV001431027	likely pathogenic	Bilateral sensorineural hearing impairment	2020-01-20	no assertion criteria provided	clinical testing	The p.Ala230Val missense variant has been reported to co-segregate with autosomal dominant non-syndromic progressive hearing loss in a large Italian family [PMID: 16449806]. The p.Ala230Val variant has also been reported in an unrelated 5-year old boy affected with moderate bilateral hearing loss [PMID: 28802369]. The variant is absent from the gnomAD database indicating that it is an extremely rare allele in the general population. The p.Ala230Val variant is predicted deleterious by various in silico prediction tools. The affected alanine residue is evolutionarily conserved and is located within the functionally important motor domain of MYO7A molecule. Missense variants in this region of the protein have been associated with autosomal dominant hearing loss. Based on the available evidence, the p.Ala230Val missense variant in the MYO7A gene is assessed as likely pathogenic.