NM_001103.4(ACTN2):c.1864G>A (p.Asp622Asn) AND not specified

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Sep 23, 2019
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:: RCV000036887.13

Allele description [Variation Report for NM_001103.4(ACTN2):c.1864G>A (p.Asp622Asn)]

NM_001103.4(ACTN2):c.1864G>A (p.Asp622Asn)

Gene:

ACTN2:actinin alpha 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_001103.4(ACTN2):c.1864G>A (p.Asp622Asn)

Other names:

p.D622N:GAT>AAT

HGVS:

NC_000001.11:g.236753971G>A
NG_009081.2:g.94831G>A
NM_001103.4:c.1864G>AMANE SELECT
NM_001278343.2:c.1864G>A
NM_001278344.2:c.1240G>A
NP_001094.1:p.Asp622Asn
NP_001094.1:p.Asp622Asn
NP_001265272.1:p.Asp622Asn
NP_001265273.1:p.Asp414Asn
LRG_436t1:c.1864G>A
LRG_436:g.94831G>A
LRG_436p1:p.Asp622Asn
NC_000001.10:g.236917271G>A
NG_009081.1:g.72502G>A
NM_001103.2:c.1864G>A
NM_001103.3:c.1864G>A
c.1864G>A

Protein change:

D414N

Links:

dbSNP: rs138452803

NCBI 1000 Genomes Browser:

rs138452803

Molecular consequence:

NM_001103.4:c.1864G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278343.2:c.1864G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278344.2:c.1240G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000060542	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Jan 29, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001362351	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Sep 23, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001919707	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000060542

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Jan 29, 2015)

germline

clinical testing

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

SCV001362351

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Sep 23, 2019)

germline

clinical testing

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

Citation Link,

SCV001919707

Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided

Benign

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	5	5	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy.

Jääskeläinen P, Vangipurapu J, Raivo J, Kuulasmaa T, Heliö T, Aalto-Setälä K, Kaartinen M, Ilveskoski E, Vanninen S, Hämäläinen L, Melin J, Kokkonen J, Nieminen MS; FinHCM Study Group., Laakso M, Kuusisto J.

ESC Heart Fail. 2019 Apr;6(2):436-445. doi: 10.1002/ehf2.12420. Epub 2019 Feb 18.

PubMed [citation]

PMID:: 30775854
PMCID:: PMC6437444

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060542.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (1)

Description

p.Asp622Asn in exon 16 of ACTN2: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (33/10562) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs138452803).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		5	not provided	5	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362351.1

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

Description

Variant summary: ACTN2 c.1864G>A (p.Asp622Asn) results in a conservative amino acid change located in the Spectrin repeat domain (IPR002017) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251418 control chromosomes. The observed variant frequency is approximately 9.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1864G>A has been reported in the literature at-least once in sequencing studies of individuals affected with Hypertrophic Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy (Jaaskelainen_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments of likely benign (n=3) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.

#	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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001919707.1

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

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

Last Updated: Sep 29, 2024

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