Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_005159.5(ACTC1):c.850A>T (p.Ile284Phe)

CA019962

45191 (ClinVar)

Gene: ACTC1 (HGNC:70)

Condition: hypertrophic cardiomyopathy (MONDO:0005045)

Inheritance Mode: Autosomal dominant inheritance

UUID: 92989cc9-1b37-431b-88dc-403615912054

Approved on: 2025-11-13

Published on: 2025-11-13

HGVS expressions

NM_005159.5(ACTC1):c.850A>T (p.Ile284Phe)

NM_005159.5:c.850A>T

NC_000015.10:g.34791254T>A

CM000677.2:g.34791254T>A

NC_000015.9:g.35083455T>A

CM000677.1:g.35083455T>A

NC_000015.8:g.32870747T>A

NG_007553.1:g.9473A>T

ENST00000560563.2:n.1750A>T

ENST00000290378.6:c.850A>T

ENST00000647798.1:n.944A>T

ENST00000650163.1:n.930A>T

ENST00000290378.4:c.850A>T

ENST00000557860.1:n.540A>T

NM_005159.4:c.850A>T

NR_120329.1:n.299+13823T>A

Likely Pathogenic

PM2_Supporting PS4_Moderate PP3 PP1_Moderate

BA1 BP4 BP1 BS4 BS1 PP2 PM1

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTC1 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

NM_005159.5(ACTC1):c.850A>T (p.Ile284Phe) - This variant has been identified in individuals with HCM as well as other cardiomyopathies (deciphergenomics.org, OMGL data, PMID 27532257) and is statistically increased in individuals with HCM compared to controls [OR lower 95% CI >10]. Therefore, the PS4_Moderate criteria has been applied. This variant segregated with disease in 3 affected relatives with HCM in 3 families and 3 affected relatives with DCM/LVNC in one family (UK Laboratories; PP1_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3). Therefore, this variant is classified as Likely Pathogenic for HCM in an autosomal dominant manner based on PS4_Moderate, PP1_Moderate, PM2_Supporting, PP3.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org).

PS4_Moderate

This variant has been reported in individuals with HCM (deciphergenomics.org, OMGL data, PMID 27532257) and is statistically increased in individuals with HCM compared to controls [OR lower 95% CI >10]. Therefore, the PS4_Moderate criteria has been applied.

PP3

Computational prediction tools suggest that this variant may impact the protein (REVEL score >0.7; PP3).

PP1_Moderate

This variant segregated with disease in 3 affected relatives with HCM in 3 families and 3 affected relatives with DCM/LVNC in one family (UK Laboratories; PP1_Moderate).

BA1