NM_005159.5(ACTC1):c.56_57insCA (p.Lys20fs) AND multiple conditions

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 30, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000460199.11

Allele description [Variation Report for NM_005159.5(ACTC1):c.56_57insCA (p.Lys20fs)]

NM_005159.5(ACTC1):c.56_57insCA (p.Lys20fs)

Genes:

GJD2-DT:GJD2 divergent transcript [Gene - HGNC]
ACTC1:actin alpha cardiac muscle 1 [Gene - OMIM - HGNC]

Variant type:

Insertion

Cytogenetic location:

15q14

Genomic location:

Preferred name:

NM_005159.5(ACTC1):c.56_57insCA (p.Lys20fs)

HGVS:

NC_000015.10:g.34794752_34794753insTG
NG_007553.1:g.5974_5975insCA
NM_005159.5:c.56_57insCAMANE SELECT
NP_005150.1:p.Lys20fs
LRG_388t1:c.56_57insCA
LRG_388:g.5974_5975insCA
NC_000015.9:g.35086953_35086954insTG
NM_005159.4:c.56_57insCA

Protein change:

K20fs

Links:

dbSNP: rs730880387

NCBI 1000 Genomes Browser:

rs730880387

Molecular consequence:

NM_005159.5:c.56_57insCA - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hypertrophic cardiomyopathy 11
Synonyms:: Familial hypertrophic cardiomyopathy 11; ACTC1-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0012799; MedGen: C2677506; OMIM: 612098

Name:: Dilated cardiomyopathy 1R (CMD1R)
Identifiers:: MONDO: MONDO:0013261; MedGen: C3150681; Orphanet: 154; Orphanet: 54260; OMIM: 613424

Name:: Atrial septal defect 5 (ASD5)
Identifiers:: MONDO: MONDO:0013011; MedGen: C2748552; Orphanet: 1478; OMIM: 612794

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000550879	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 30, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34495297, 28492532
SCV002800823	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 28, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000550879

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 30, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002800823

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 28, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.

Yoneda ZT, Anderson KC, Quintana JA, O'Neill MJ, Sims RA, Glazer AM, Shaffer CM, Crawford DM, Stricker T, Ye F, Wells Q, Stevenson LW, Michaud GF, Darbar D, Lubitz SA, Ellinor PT, Roden DM, Shoemaker MB.

JAMA Cardiol. 2021 Dec 1;6(12):1371-1379. doi: 10.1001/jamacardio.2021.3370.

PubMed [citation]

PMID:: 34495297
PMCID:: PMC8427496

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000550879.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Lys20Argfs*38) in the ACTC1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ACTC1 cause disease. This variant is present in population databases (rs730880387, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with atrial fibrillation (PMID: 34495297). ClinVar contains an entry for this variant (Variation ID: 180752). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002800823.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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