Submissions for variant NM_020297.4(ABCC9):c.3460C>T (p.Arg1154Trp)

dbSNP: rs387907208

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute	RCV000024624	SCV000538206	pathogenic	Hypertrichotic osteochondrodysplasia Cantu type	2015-12-15	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546897	SCV000639233	pathogenic	Dilated cardiomyopathy 1O	2023-02-11	criteria provided, single submitter	clinical testing	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. This variant is not present in population databases (gnomAD no frequency). 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). ClinVar contains an entry for this variant (Variation ID: 31946). For these reasons, this variant has been classified as Pathogenic. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000024624	SCV001429923	pathogenic	Hypertrichotic osteochondrodysplasia Cantu type	2020-02-25	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270102	SCV001448926	pathogenic	Epicanthus; Micrognathia; Tapered finger; Coarse facial features; Abnormal facial shape; Bulbous nose; Depressed nasal bridge; Thick upper lip vermilion; Macrocephaly; Abnormality of the face; Low anterior hairline; Large hands; Joint hypermobility; Left ventricular hypertrophy; Patent ductus arteriosus	2018-06-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000024624	SCV001451475	pathogenic	Hypertrichotic osteochondrodysplasia Cantu type	2019-08-30	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001570693	SCV001795028	pathogenic	not provided	2022-06-27	criteria provided, single submitter	clinical testing	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)
Suma Genomics	RCV000024624	SCV001837611	likely pathogenic	Hypertrichotic osteochondrodysplasia Cantu type		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001570693	SCV002018662	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004545734	SCV004046112	pathogenic	ABCC9-related disorder		criteria provided, single submitter	clinical testing	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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001570693	SCV005199095	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000024624	SCV000050490	pathogenic	Hypertrichotic osteochondrodysplasia Cantu type	2012-06-08	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001570693	SCV001927352	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001570693	SCV001954099	pathogenic	not provided		no assertion criteria provided	clinical testing