rs121912560
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePP3_StrongPP5_Very_Strong
The NM_004999.4(MYO6):āc.737A>Gā(p.His246Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_004999.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO6 | NM_004999.4 | c.737A>G | p.His246Arg | missense_variant | 9/35 | ENST00000369977.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO6 | ENST00000369977.8 | c.737A>G | p.His246Arg | missense_variant | 9/35 | 1 | NM_004999.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250992Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135728
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461670Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727146
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 246 of the MYO6 protein (p.His246Arg). This variant is present in population databases (rs121912560, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 15060111). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8581). 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 MYO6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 01, 2023 | Not observed at significant frequency 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: 15060111, 18212818, 18348273, 29044474, 29224747, 27535533, 34662886) - |
Sensorineural deafness with hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2004 | - - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 30, 2015 | The p.His246Arg variant in MYO6 has been reported in one individual with progres sive, post-lingual sensorineural hearing loss and left ventricular hypertrophy ( LVH), and it segregated with hearing loss in 9 affected relatives (Mohiddin 2004 ). Two family members (ages 12 and 28 years) carried the variant but did not hav e hearing loss, which may reflect reduced penetrance or variable onset. Alternat ively, of the 11 family members that carried the p.His246Arg variant, only 4 ind ividuals presented with cardiac hypertrophy, while another 3 family members were reported to have an abnormal ECG. While this could also indicate reduced penetr ance of LVH, given that no other variant in the MYO6 gene has been associated wi th cardiac hypertrophy, it is possible that the LVH in the family is caused by a n unrelated etiology. Of note, one family member who did not carry the variant a nd did not have sensorineural hearing loss was reported to have LVH which indica tes that this MYO6 variant does not segregate with that manifestation; however, the authors attributed this individual's cardiac features to valvar and ischaemi c disease. The variant was absent in population databases. In summary, although additional studies are required to fully establish its clinical significance, th is variant is likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at