rs387907228

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_020297.4(ABCC9):​c.3346C>T​(p.Arg1116Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1116G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ABCC9
NM_020297.4 missense

Scores

11
7
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.64
Variant links:
Genes affected
ABCC9 (HGNC:60): (ATP binding cassette subfamily C member 9) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein is thought to form ATP-sensitive potassium channels in cardiac, skeletal, and vascular and non-vascular smooth muscle. Protein structure suggests a role as the drug-binding channel-modulating subunit of the extra-pancreatic ATP-sensitive potassium channels. Mutations in this gene are associated with cardiomyopathy dilated type 1O. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 71) in uniprot entity ABCC9_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_020297.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-21842441-G-C is described in Lovd as [Pathogenic].
PP2
Missense variant in the ABCC9 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 4.9694 (above the threshold of 3.09). Trascript score misZ: 7.023 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrichotic osteochondrodysplasia Cantu type, dilated cardiomyopathy, acromegaloid facial appearance syndrome, Brugada syndrome, atrial fibrillation, familial, 12, intellectual disability and myopathy syndrome, dilated cardiomyopathy 1O, familial isolated dilated cardiomyopathy, hypertrichosis-acromegaloid facial appearance syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.871
PP5
Variant 12-21842441-G-A is Pathogenic according to our data. Variant chr12-21842441-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21842441-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCC9NM_020297.4 linkc.3346C>T p.Arg1116Cys missense_variant Exon 29 of 40 ENST00000261200.9 NP_064693.2 O60706-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCC9ENST00000261200.9 linkc.3346C>T p.Arg1116Cys missense_variant Exon 29 of 40 5 NM_020297.4 ENSP00000261200.4 O60706-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 07, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27316244, 21344641, 32371413, 34056838, 22610116, 31828977) -

Hypertrichotic osteochondrodysplasia Cantu type Pathogenic:2
May 18, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

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Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dilated cardiomyopathy 1O Pathogenic:1
Jan 09, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1116 amino acid residue in ABCC9. Other variant(s) that disrupt this residue have been observed in individuals with ABCC9-related conditions (PMID: 25590979, 23307537, 22610116), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in individuals with Cantu syndrome and observed to segregate with clinical features of Cantu syndrome in a family, and observed de novo in an individual with clinical features of Cantu syndrome (PMID: 22610116, 27316244, Invitae). ClinVar contains an entry for this variant (Variation ID: 35534). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 1116 of the ABCC9 protein (p.Arg1116Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. -

Kleefstra syndrome 1 Pathogenic:1
Jun 11, 2018
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

[ACMG/AMP: PM2, PM5, PP2, PP3, PP5] This alteration is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -

Cardiovascular phenotype Pathogenic:1
Sep 11, 2019
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R1116C variant (also known as c.3346C>T), located in coding exon 27 of the ABCC9 gene, results from a C to T substitution at nucleotide position 3346. The arginine at codon 1116 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals reported to have Cantú syndrome, and was reported to segregate with Cantú syndrome-associated features in one family (Harakalova M et al. Nat. Genet., 2012 May;44:793-6; Leon Guerrero CR et al. Neurology, 2016 07;87:270-6). A different variant affecting this codon (p.R1116H, c.3347G>A) has also been reported in association with Cantú syndrome, including de novo occurrence (Harakalova M et al. Nat. Genet., 2012 May;44:793-6; Czeschik JC et al. Am. J. Med. Genet. A, 2013 Feb;161A:295-300; Zhu X et al. Genet. Med., 2015 Oct;17:774-81). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
.;.;D
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.87
D;D;D
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Uncertain
2.9
M;.;M
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-4.5
D;D;D
REVEL
Pathogenic
0.78
Sift
Uncertain
0.014
D;D;D
Sift4G
Uncertain
0.012
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.91
MutPred
0.70
Loss of disorder (P = 0.0362);.;Loss of disorder (P = 0.0362);
MVP
0.96
MPC
1.9
ClinPred
0.99
D
GERP RS
5.3
Varity_R
0.65
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs387907228; hg19: chr12-21995375; COSMIC: COSV53983185; API