Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001100.4:c.1092del

CA915940544

Gene: ACTA1
Condition: alpha-actinopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: fff69479-7ace-4acd-94b4-11a691824794
Approved on: 2024-08-07
Published on: 2024-12-19

HGVS expressions

NM_001100.4:c.1092del
NC_000001.11:g.229431541del
CM000663.2:g.229431541del
NC_000001.10:g.229567288del
CM000663.1:g.229567288del
NC_000001.9:g.227633911del
NG_006672.1:g.7556del
ENST00000366683.4:c.1014del
ENST00000684723.1:c.957del
ENST00000366683.3:c.723del
ENST00000366684.7:c.1092del
NM_001100.3:c.1092del
More

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PVS1_Strong PP4 PM3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The c.1092delC (p.Tyr364*) variant in ACTA1 is a deletion variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 363-377) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMIDs:16945536, 17187373). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been detected in one homozygous individual with features consistent with nemaline myopathy, including a muscle biopsy with multiple small nemaline rods in most fibers (PM3, PP4 PMID:17187373). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3, PM2_Supporting, PP4 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024).
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PVS1_Strong
The c.1092delC (p.Tyr364*) variant in ACTA1 is a deletion variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 363-377) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMIDs:16945536, 17187373).
PP4
This variant has been detected in one homozygous individual with features consistent with nemaline myopathy, including a muscle biopsy with multiple small nemaline rods in most fibers (PM3, PP4 PMID:17187373).
PM3
This variant has been detected in one homozygous individual with features consistent with nemaline myopathy, including a muscle biopsy with multiple small nemaline rods in most fibers (PM3, PP4 PMID:17187373).
Curation History
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