NM_020297.4(ABCC9):c.4512+814C>T AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 26, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001375633.8

Allele description [Variation Report for NM_020297.4(ABCC9):c.4512+814C>T]

NM_020297.4(ABCC9):c.4512+814C>T

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

12p12.1

Genomic location:

Preferred name:

NM_020297.4(ABCC9):c.4512+814C>T

HGVS:

NC_000012.12:g.21805184G>A
NG_012819.1:g.136511C>T
NM_001377273.1:c.4512+814C>T
NM_001377274.1:c.3645+814C>T
NM_005691.4:c.4640C>T
NM_020297.4:c.4512+814C>TMANE SELECT
NP_005682.2:p.Thr1547Ile
LRG_377t1:c.4512+814C>T
LRG_377t2:c.4640C>T
LRG_377:g.136511C>T
NC_000012.11:g.21958118G>A
NM_005691.2:c.4640C>T
NM_020297.2:c.4512+814C>T
O60706:p.Thr1547Ile

Protein change:

T1547I; THR1547ILE

Links:

UniProtKB: O60706#VAR_066210; OMIM: 601439.0003; dbSNP: rs387906805

NCBI 1000 Genomes Browser:

rs387906805

Molecular consequence:

NM_001377273.1:c.4512+814C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001377274.1:c.3645+814C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_020297.4:c.4512+814C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_005691.4:c.4640C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001572558	Loeys Lab, Universiteit Antwerpen	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 26, 2021)	maternal	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17245405, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001572558

Loeys Lab, Universiteit Antwerpen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 26, 2021)

maternal

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	maternal	yes	2	1	not provided	4	yes	clinical testing

Citations

PubMed

KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation.

Olson TM, Alekseev AE, Moreau C, Liu XK, Zingman LV, Miki T, Seino S, Asirvatham SJ, Jahangir A, Terzic A.

Nat Clin Pract Cardiovasc Med. 2007 Feb;4(2):110-6.

PubMed [citation]

PMID:: 17245405
PMCID:: PMC2013306

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Loeys Lab, Universiteit Antwerpen, SCV001572558.1

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

Description

This sequence change results in a missense variant in the ABCC9 gene (p.(Thr1547Ile)). This variant is not present in population databases (absent from GnomAD; PM2). This variant has been reported in the literature in individuals with atrial fibrillation(Olsen et. al; 2007). Functional data are available: Patch-clamp analysis demonstrated that the variant compromised ATP-dependent induction of K-current. Kir6.2-Knock-out mice developed AF in response to adrenergic stimulus. (Olsen et. al; 2007; PS3). Prediction programs showed conflicting results (Align GVGD: G0; PolyPhen-2HumDiv and HumVar: benign; SIFT: tolerated; Mutation taster: disease causing). The variant affects a highly conserved nucleotide and weakly conserved amino acid. The variant was identified in a family with HCM, however it did not show segregation with the HCM-phenotype (BS4). In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (Conflicting results: PM2,PS3, BS4).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	4	Blood	not provided		2	not provided	1	not provided

Last Updated: Nov 10, 2024

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