Submissions for variant NM_004999.4(MYO6):c.238C>T (p.Arg80Ter)

gnomAD frequency: 0.00001  dbSNP: rs727504567

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000155733	SCV000840523	pathogenic	Nonsyndromic genetic hearing loss	2023-01-24	reviewed by expert panel	curation	The NM_004999.4:c.238C>T (p.Arg80Ter) variant in MYO6 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008% (1/113330 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<=0.002%) for PM2_Supporting. This variant has been reported in 2 families with teenage onset progressive sensorineural hearing loss, both displaying an autosomal dominant pattern of inheritance (PS4_Supporting; PMID: 32143290, 33111345). The variant has been reported to segregate with hearing loss in 2 affected family members from 1 family (PP1; PMID:33111345). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PVS1, PM2_Supporting, PS4_Supporting, PP1). (VCEP specifications version 2.0.0; December 21, 2022)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844712	SCV000205443	likely pathogenic	Rare genetic deafness	2013-10-05	criteria provided, single submitter	clinical testing	The Arg80X variant in MYO6 has not been reported in individuals with hearing los s or in large population studies. This nonsense variant leads to a premature ter mination codon at position 80, which is predicted to lead to a truncated or abse nt protein. Nonsense variants in the MYO6 gene have been reported as disease cau sing variants in families with hearing loss. In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinic al significance.
GeneDx	RCV000480356	SCV000570574	likely pathogenic	not provided	2020-01-10	criteria provided, single submitter	clinical testing	Reported as a variant identified in the Deafness Variation Database, however, no additional information was provided (Sampaio-Silva et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29044474, 32143290, 33111345)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507733	SCV000604424	likely pathogenic	not specified	2017-01-26	criteria provided, single submitter	clinical testing
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV001004798	SCV001164286	pathogenic	Autosomal dominant nonsyndromic hearing loss 22	2018-05-07	criteria provided, single submitter	research	Dominant, teenage onset, progressive moderate high tone NSHL