Submissions for variant NM_001145809.2(MYH14):c.526G>A (p.Ala176Thr)

gnomAD frequency: 0.00014  dbSNP: rs138001307

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220639	SCV000272008	uncertain significance	not specified	2015-06-01	criteria provided, single submitter	clinical testing	The p.Ala176Thr variant in MYH14 has not been previously reported in individuals with hearing loss. This variant has been identified in 0.03% 18/67222 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs138001307). Although this variant has been seen in the general p opulation, its frequency is not high enough to rule out a pathogenic role. Compu tational prediction tools and conservation analyses suggest that the p.Ala176Thr variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, the clinical significance of the p.Ala 176Thr variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000404566	SCV000414372	uncertain significance	Autosomal dominant nonsyndromic hearing loss 4A	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756388	SCV000884183	uncertain significance	not provided	2017-08-23	criteria provided, single submitter	clinical testing	The p.Ala176Thr variant has not been reported in the medical literature, and is not listed in gene-specific variant databases. It has been previously identified in our laboratory in an individual with suspected sensorineural hearing loss. The p.Ala176Thr variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.028% in the non-Finnish European population (identified in 31 out of 111,448 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 228878). The alanine at codon 176 is highly conserved considering 7 species up to cow (Alamut software v2.9.0), and computational analyses suggest that this variant affects the MYH14 protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Ala176Thr variant cannot be determined with certainty.
CeGaT Center for Human Genetics Tuebingen	RCV000756388	SCV000892276	uncertain significance	not provided	2018-05-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000756388	SCV001779056	likely benign	not provided	2020-11-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27610647)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000756388	SCV002245270	likely benign	not provided	2023-04-15	criteria provided, single submitter	clinical testing
Miami Human Genetics, University Of Miami Miller School Of Medicine	RCV000404566	SCV003928163	uncertain significance	Autosomal dominant nonsyndromic hearing loss 4A	2023-06-02	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000220639	SCV005039288	uncertain significance	not specified	2024-03-21	criteria provided, single submitter	clinical testing	Variant summary: MYH14 c.526G>A (p.Ala176Thr) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of 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 0.00017 in 248994 control chromosomes (gnomAD). c.526G>A has been reported in the literature in at least one individual affected with Deafness, Autosomal Dominant 4 (Chen_2016). The report does not provide unequivocal conclusions about association of the variant with Deafness, Autosomal Dominant 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27610647, 34681017). ClinVar contains an entry for this variant (Variation ID: 228878). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000404566	SCV005073763	pathogenic	Autosomal dominant nonsyndromic hearing loss 4A	2024-05-30	criteria provided, single submitter	research	Pathogenic by Deafness Variatiob Database based on PMID: 27610647
Center for Computational Biology & Bioinformatics, University of California, San Diego	RCV004567498	SCV005050060	uncertain significance	Meniere disease	2024-06-03	no assertion criteria provided	research