NM_001103.4(ACTN2):c.1484C>T (p.Thr495Met) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 7, 2022
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:: RCV000036880.9

Allele description [Variation Report for NM_001103.4(ACTN2):c.1484C>T (p.Thr495Met)]

NM_001103.4(ACTN2):c.1484C>T (p.Thr495Met)

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.1484C>T (p.Thr495Met)

HGVS:

NC_000001.11:g.236747744C>T
NG_009081.2:g.88604C>T
NM_001103.4:c.1484C>TMANE SELECT
NM_001278343.2:c.1484C>T
NM_001278344.2:c.860C>T
NP_001094.1:p.Thr495Met
NP_001094.1:p.Thr495Met
NP_001265272.1:p.Thr495Met
NP_001265273.1:p.Thr287Met
LRG_436t1:c.1484C>T
LRG_436:g.88604C>T
LRG_436p1:p.Thr495Met
NC_000001.10:g.236911044C>T
NG_009081.1:g.66275C>T
NM_001103.2:c.1484C>T
NM_001103.3:c.1484C>T
P35609:p.Thr495Met
c.1484C>T

Protein change:

T287M; THR495MET

Links:

UniProtKB: P35609#VAR_071971; OMIM: 102573.0003; dbSNP: rs200248944

NCBI 1000 Genomes Browser:

rs200248944

Molecular consequence:

NM_001103.4:c.1484C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001278343.2:c.1484C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001278344.2:c.860C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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ATP synthase CF0 B subunit (chloroplast) [Eucalyptus globulus subsp. globulus]
ATP synthase CF0 B subunit (chloroplast) [Eucalyptus globulus subsp. globulus]
gi|108802629|ref|YP_636285.1|

Protein
Sulfurimonas sp. M-112 napA gene for nitrate reductase catalytic subunit, partia...
Sulfurimonas sp. M-112 napA gene for nitrate reductase catalytic subunit, partial cds
gi|1172208742|dbj|AB697430.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000060535	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jun 16, 2016)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 20022194, 17097056, 23861362, 23299917, 24082139, 24033266
SCV002500165	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Mar 7, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20022194, 26084686, 32880476, 17097056 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000060535

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jun 16, 2016)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002500165

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Mar 7, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	4	4	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

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program..

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]

PMID:: 23861362
PMCID:: PMC3887521

New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.

Andreasen C, Nielsen JB, Refsgaard L, Holst AG, Christensen AH, Andreasen L, Sajadieh A, Haunsø S, Svendsen JH, Olesen MS.

Eur J Hum Genet. 2013 Sep;21(9):918-28. doi: 10.1038/ejhg.2012.283. Epub 2013 Jan 9.

PubMed [citation]

PMID:: 23299917
PMCID:: PMC3746259

See all PubMed Citations (8)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060535.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Thr495Met variant in ACTN2 has been reported in at least 3 individuals wit h HCM, segregating with disease in 1 affected relative (Theis 2006, Chiu 2010). This variant has been previously identified by our laboratory in 3 individuals w ith HCM, one of which also carried a pathogenic variant in another gene. In addi tion, the p.Thr495Met variant in ACTN2 did not segregate with disease in two aff ected relatives from one family. This variant has also been identified in 22/651 34 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs200248944). Computational prediction tools and conser vation analysis suggest that this variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, due t o conflicting data, the clinical significance of the p.Thr495Met variant is unce rtain.

#	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		4	not provided	4	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002500165.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: ACTN2 c.1484C>T (p.Thr495Met) results in a non-conservative amino acid change in 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 0.00028 in 251310 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 11 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.1484C>T has been reported in the literature in an individual with Z-disk HCM within a cohort previously determined to be negative for mutations in the eight genes associated with myofilament-HCM (example, Theis_2006), in two individuals from a single family reportedly affected by HCM who were only screened for ACTN2 by high melt analysis (example, Chiu_2010), and as a VUS in settings of multigene panel testing in at-least two individuals among DCM cohorts (example, Akinrinade_2015, Verdonschot_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic/Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4; likely benign, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly 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

Last Updated: Nov 3, 2024

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