rs876657911
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5
The NM_004999.4(MYO6):c.3610C>T(p.Arg1204Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,888 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004999.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251452Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135896
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727248
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18348273, 18212818, 23635807, 12687499, 24123792, 28000701, 33710140, 23340379, 38400873, 35661827, 39019031) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 31, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1204 of the MYO6 protein (p.Arg1204Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with deafness (PMID: 23340379, 33710140). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228996). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 04, 2015 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1204Tr p variant in MYO6 has been reported in 1 Dutch individual with hearing loss and segregated with disease in 9 affected family members (Oonk 2013). However, thre e unaffected individuals under or around the reported mean age of onset (38 yrs) also carried the variant, and the proband in this family had a different phenot ype than the other 9 affected family members with a much earlier age of onset an d more severe hearing impairment. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that t he Arg1204Trp variant may impact the protein, though this information is not pre dictive enough to determine pathogenicity. In summary, while there is some suspi cion for a pathogenic role, the clinical significance of this variant is uncerta in due to inconsistencies in the segregation and age of onset reported for the D utch family described above. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at