NM_020297.4(ABCC9):c.4512+744_4512+746delinsAAAT AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 11, 2021
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:: RCV000601900.5

Allele description [Variation Report for NM_020297.4(ABCC9):c.4512+744_4512+746delinsAAAT]

NM_020297.4(ABCC9):c.4512+744_4512+746delinsAAAT

Gene:

ABCC9:ATP binding cassette subfamily C member 9 [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

12p12.1

Genomic location:

Preferred name:

NM_020297.4(ABCC9):c.4512+744_4512+746delinsAAAT

HGVS:

NC_000012.12:g.21805252_21805254delinsATTT
NG_012819.1:g.136441_136443delinsAAAT
NM_001377273.1:c.4512+744_4512+746delinsAAAT
NM_001377274.1:c.3645+744_3645+746delinsAAAT
NM_005691.4:c.4570_4572delinsAAAT
NM_020297.4:c.4512+744_4512+746delinsAAATMANE SELECT
NP_005682.2:p.Leu1524fs
LRG_377t2:c.4570_4572delTTAinsAAAT
LRG_377:g.136441_136443delinsAAAT
NC_000012.11:g.21958186_21958188delinsATTT
NM_005691.2:c.4570_4572delTTAinsAAAT
NM_005691.3:c.4570_4572delTTAinsAAAT
p.Leu1524Lysfs*5
p.Leu1524LysfsX5

Protein change:

L1524fs

Links:

OMIM: 601439.0001; dbSNP: rs869025349

NCBI 1000 Genomes Browser:

rs869025349

Molecular consequence:

NM_005691.4:c.4570_4572delinsAAAT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377273.1:c.4512+744_4512+746delinsAAAT - intron variant - [Sequence Ontology: SO:0001627]
NM_001377274.1:c.3645+744_3645+746delinsAAAT - intron variant - [Sequence Ontology: SO:0001627]
NM_020297.4:c.4512+744_4512+746delinsAAAT - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000711368	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (May 18, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15034580, 24439875, 26899768, 24033266
SCV002014872	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 11, 2021)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 15034580, 23861362, 24439875, 22337857, 21846889, 26899768, 28600387, 30847666, 31638414, 32972544, 20664073, 31030551, 20033705, 18497752 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000711368

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(May 18, 2018)

germline

clinical testing

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

SCV002014872

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 11, 2021)

germline

clinical testing

PubMed (14)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	2	2	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

ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating.

Bienengraeber M, Olson TM, Selivanov VA, Kathmann EC, O'Cochlain F, Gao F, Karger AB, Ballew JD, Hodgson DM, Zingman LV, Pang YP, Alekseev AE, Terzic A.

Nat Genet. 2004 Apr;36(4):382-7. Epub 2004 Mar 21.

PubMed [citation]

PMID:: 15034580
PMCID:: PMC1995438

See all PubMed Citations (15)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711368.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (4)

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Leu1524fs var iant in ABCC9 has been reported in 2 individuals with DCM (Bienengraeber 2004, C uenca 2016) and 1 individual with Brugada Syndrome (Hu 2014), but has also been identified in 0.08% (107/126560) of European chromosomes by the Genome Aggregati on Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs139703258 and rs7 61784169). In vitro functional studies provide some evidence that the p.Leu1524f s variant may impact protein function (Bienengraeber et al. 2004); however, thes e types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein?s amino acid seque nce beginning at position 1524 and leads to a premature termination codon 5 amin o acids downstream. This termination codon occurs within the last exon of the ge ne and is likely to escape nonsense mediated decay, resulting in a truncated pro tein. In summary, while the clinical significance of the p.Leu1524fs variant is uncertain, the frequency data suggests that it is more likely to be benign. ACMG /AMP Criteria applied. BS1, PS3_Supporting.

#	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		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002014872.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

Variant summary: ABCC9 c.4570_4572delinsAAAT (p.Leu1524LysfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was reported as two separate changes ((c.4571_4572delTA (p.Leu1524CysfsTer4) and c.4569_4570insAAA (p.Ile1523_Leu1524insLys)) in gnomAD and the variant allele was found at a frequency of 0.00051 in 283858 control chromosomes, predominantly at a frequency of 0.00085 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 54 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC9 causing Dilated Cardiomyopathy phenotype (1.6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4570_4572delinsAAAT has been reported in the literature in individuals affected with idiopathic Dilated Cardiomyopathy, Brugada syndrome, very early onset Atrial Fibrillation as well as in individuals who were analyzed for arrhythmia gene panel and diagnosis was unknown arrhythmia (Bienengraeber_2004, Hu_2013, Mellor_2017, van Lint_2019, Goodyer_2019). At least one functional study reports experimental evidence evaluating an impact on protein function and this variant results in reducing the catalytic activity of NBD2 and physiological activation of the channel (Bienengraeber_2004). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional clinical and functional evidence become available.

#	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: Sep 29, 2024

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