rs727504567
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1PM2_SupportingPS4_SupportingPVS1
This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA183381/MONDO:0019497/005
Frequency
Consequence
NM_004999.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO6 | NM_004999.4 | c.238C>T | p.Arg80Ter | stop_gained | 4/35 | ENST00000369977.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO6 | ENST00000369977.8 | c.238C>T | p.Arg80Ter | stop_gained | 4/35 | 1 | NM_004999.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151930Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250810Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135606
GnomAD4 exome AF: 0.00000140 AC: 2AN: 1429714Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1AN XY: 713240
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151930Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74180
ClinVar
Submissions by phenotype
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 26, 2017 | - - |
Nonsyndromic genetic hearing loss Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Jan 24, 2023 | 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) - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 10, 2020 | 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) - |
Autosomal dominant nonsyndromic hearing loss 22 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | May 07, 2018 | Dominant, teenage onset, progressive moderate high tone NSHL - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 05, 2013 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at