rs387907208

Positions:

Variant summary

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

The NM_020297.4(ABCC9):c.3460C>T(p.Arg1154Trp) 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. R1154Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ABCC9
NM_020297.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 3.66

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]

ABCC9 links:

ABCC9 (HGNC:):

ABCC9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a topological_domain Extracellular (size 96) in uniprot entity ABCC9_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) 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 chr12-21842326-C-T is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ABCC9. . Gene score misZ 4.9694 (greater than the threshold 3.09). Trascript score misZ 7.023 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.904

PP5

Variant 12-21842327-G-A is Pathogenic according to our data. Variant chr12-21842327-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21842327-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC9	NM_020297.4 linkuse as main transcript	c.3460C>T	p.Arg1154Trp	missense_variant	29/40	ENST00000261200.9	NP_064693.2	O60706-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9 linkuse as main transcript	c.3460C>T	p.Arg1154Trp	missense_variant	29/40	5	NM_020297.4	ENSP00000261200.4		O60706-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727112

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrichotic osteochondrodysplasia Cantu type

Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 08, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 25, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 30, 2019	The ABCC9 c.3640C>T (p.Arg1154Trp) variant is a missense variant that is located in the second transmembrane domain of ABCC9. This variant has been reported in a heterozygous de novo state in five unrelated individuals with Cantu syndrome (van Bon et al. 2012; Harakalova et al. 2012; Afifi et al. 2016). The p.Arg1154Trp variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. Another missense change at the same residue, p.Arg1154Gln, has also been reported to be pathogenic for Cantu syndrome (van Bon et al. 2012; Harakalova et al. 2012). Based on the collective evidence and the application of the ACMG criteria, the p.Arg1154Trp variant is classified as pathogenic for Cantu syndrome. -
Pathogenic, criteria provided, single submitter	research	Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute	Dec 15, 2015	- -

not provided

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26656175, 28690487, 27316244, 29275331, 31030551, 31828977, 34056838, 32065455, 25790160, 26871653, 22610116, 22608503) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 01, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Dilated cardiomyopathy 1O

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 11, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1154 of the ABCC9 protein (p.Arg1154Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Cantu syndrome (PMID: 22608503, 22610116, 25790160, 26656175, 26871653). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 31946). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC9 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg1154 amino acid residue in ABCC9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22608503, 22610116, 23307537). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

ABCC9-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant has been previously reported as a heterozygous change in patients with Cantu syndrome (PMID: 22608503, 22610116, 25790160, 26871653, 26656175, 28690487, 31828977, 32065455, 34453476). The c.3460C>T (p.Arg1154Trp) variant is located in a mutational hotspot for pathogenic variations associated with Cantu syndrome (PMID: 22608503). Different amino acid changes at the same residue (p.R1154G and p.R1154Q) have been previously reported in individuals with Cantu syndrome (PMID: 31828977, 32065455, 32371413, 32622958, 23307537). Experimental studies showed that this change caused abnormal potassium channel function (PMID: 22610116). The c.3460C>T (p.Arg1154Trp) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.3460C>T (p.Arg1154Trp) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3460C>T (p.Arg1154Trp) variant is classified as Pathogenic. -

Patent ductus arteriosus;C0025990:Micrognathia;C0149721:Left ventricular hypertrophy;C0240543:Bulbous nose;C0424503:Abnormal facial shape;C0426870:Large hands;C0426886:Tapered finger;C0678230:Epicanthus;C1836542:Depressed nasal bridge;C1842366:Low anterior hairline;C1844820:Joint hypermobility;C1845847:Coarse facial features;C1846423:Thick upper lip vermilion;C2243051:Macrocephaly;C4025871:Abnormality of the face

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jun 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

.;.;D

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.2

M;.;M

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.022

D;D;D

Sift4G

Uncertain

0.021

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.79

MutPred

0.76

Loss of disorder (P = 0.0359);.;Loss of disorder (P = 0.0359);

MVP

0.96

MPC

1.7

ClinPred

0.99

GERP RS

4.1

Varity_R

0.90

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.31

Position offset: -13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over