Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_001614.5(ACTG1):c.608C>T(p.Thr203Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T203K) has been classified as Pathogenic.
ACTG1 (HGNC:144): (actin gamma 1) Actins are highly conserved proteins that are involved in various types of cell motility and in maintenance of the cytoskeleton. Three main groups of actin isoforms have been identified in vertebrate animals: alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton and as mediators of internal cell motility. Actin gamma 1, encoded by this gene, is a cytoplasmic actin found in all cell types. Mutations in this gene are associated with DFNA20/26, a subtype of autosomal dominant non-syndromic sensorineural progressive hearing loss and also with Baraitser-Winter syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]
ACTG1 Gene-Disease associations (from GenCC):
Baraitser-winter syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Our verdict: Pathogenic. The variant received 10 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001614.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-81511382-G-T is described in CliVar as Pathogenic. Clinvar id is 29588.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894
PP5
Variant 17-81511382-G-A is Pathogenic according to our data. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511382-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 803470.Status of the report is criteria_provided_single_submitter, 1 stars.
Loss of phosphorylation at T203 (P = 0.0176);Loss of phosphorylation at T203 (P = 0.0176);Loss of phosphorylation at T203 (P = 0.0176);Loss of phosphorylation at T203 (P = 0.0176);Loss of phosphorylation at T203 (P = 0.0176);Loss of phosphorylation at T203 (P = 0.0176);.;Loss of phosphorylation at T203 (P = 0.0176);Loss of phosphorylation at T203 (P = 0.0176);