VCV000031946.27 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 31946 Accession: VCV000031946.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p12.1 12: 21842327 (GRCh38) [ NCBI UCSC ] 12: 21995261 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Aug 25, 2024	Feb 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020297.4:c.3460C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_064693.2:p.Arg1154Trp	missense
NM_001377273.1:c.3460C>T	NP_001364202.1:p.Arg1154Trp	missense
NM_001377274.1:c.2593C>T	NP_001364203.1:p.Arg865Trp	missense
NM_005691.2:c.3460C>T
NM_005691.4:c.3460C>T	NP_005682.2:p.Arg1154Trp	missense
NC_000012.12:g.21842327G>A
NC_000012.11:g.21995261G>A
NG_012819.1:g.99368C>T
LRG_377:g.99368C>T
LRG_377t1:c.3460C>T
	O60706:p.Arg1154Trp

... more HGVS ... less HGVS

Protein change

R1154W, R865W

Other names

Canonical SPDI

NC_000012.12:21842326:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA260058 UniProtKB: O60706#VAR_068497 OMIM: 601439.0004 dbSNP: rs387907208 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCC9		-	-	GRCh38 GRCh37	1752	1796

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hypertrichotic osteochondrodysplasia Cantu type	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Feb 25, 2020	RCV000024624.17
Abnormal facial shape Abnormality of the face Bulbous nose Coarse facial features Depressed nasal bridge Epicanthus Joint hypermobility Large hands Left ventricular hypertrophy Low anterior hairline Macrocephaly Micrognathia Patent ductus arteriosus Tapered finger Thick upper lip vermilion	Pathogenic (1)	criteria provided, single submitter	Jun 4, 2018	RCV001270102.2
Dilated cardiomyopathy 1O	Pathogenic (1)	criteria provided, single submitter	Feb 11, 2023	RCV000546897.8
not provided	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2023	RCV001570693.12
ABCC9-related disorder	Pathogenic (1)	criteria provided, single submitter	-	RCV004545734.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 04, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thick upper lip vermilion Large hands Left ventricular hypertrophy Low anterior hairline Tapered finger Bulbous nose Joint hypermobility Patent ductus arteriosus Coarse facial features Macrocephaly Epicanthus Depressed nasal bridge Micrognathia Abnormal facial shape Abnormality of the face Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448926.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Clinical Features: Ascending aortic dilation (present) , Chronic constipation (present) , Disproportionate tall stature (present) , Decreased adipose tissue (present) , Generalized hypertrichosis (present) , Gingival fibromatosis … (more) Ascending aortic dilation (present) , Chronic constipation (present) , Disproportionate tall stature (present) , Decreased adipose tissue (present) , Generalized hypertrichosis (present) , Gingival fibromatosis (present) , Coarse facial features (present) , Abnormal facial shape (present) , Moon facies (present) , Thick upper lip vermilion (present) , Fatigable weakness of skeletal muscles (present) , Tall stature (present) , Tapered finger (present) , Seborrheic dermatitis (present) , Myopia (disease) (present) , Abnormality of the endocrine system (present) , Hypoplasia of the vagina (present) , Abnormality of the pinna (present) , Lumbar scoliosis (present) , Sleep disturbance (present) , Muscle cramps (present) , Premature birth (present) , Fatigue (present) , Pes cavus (present) , Joint hypermobility (present) , Talipes (present) , Slender long bone (present) , Telecanthus (present) , Epicanthus (present) , Depressed nasal bridge (present) , Broad nasal tip (present) , Bulbous nose (present) , High, narrow palate (present) , Micrognathia (present) , Dental crowding (present) , Small forehead (present) , Low anterior hairline (present) , Striae distensae (present) , Varicose veins (present) , Acne (present) , Congenital microcephaly (present) , Macrocephalus (present) , Abnormal facial shape (present) , Abnormality of the face (present) , Global developmental delay (present) , Palpebral thickening (present) , Large hands (present) , Coarse facial features (present) , Mixed hearing impairment (present) , Peripheral edema (present) , Growth delay (present) , Menstrual irregularities (present) , Psychosis (present) , Patent ductus arteriosus (present) , Left ventricular hypertrophy (present) , Abnormality of the right ventricle (present) , Abnormal venous morphology (present) , Muscular dystrophy (present) , Headache (present) , Gastroesophageal reflux (present) , Cutaneous hamartoma (present) , Trichoepithelioma (present) , Apnea (present) (less) Sex: female
Pathogenic (Jun 27, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001795028.3 First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ABCC9-related disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046112.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: 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). … (more) 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. (less)
Pathogenic (Feb 11, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dilated cardiomyopathy 1O Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000639233.4 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 22608503‚ 22610116‚ 25790160‚ 26656175‚ 26871653‚ 23307537 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 15, 2015)	criteria provided, single submitter (STSI_classification_crtieria_for_IDIOM) Method: research	Hypertrichotic osteochondrodysplasia Affected status: yes Allele origin: de novo	Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute Study: IDIOM Accession: SCV000538206.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Number of individuals with the variant: 1 Clinical Features: Hypertrichosis (present) , Intellectual disability (present) , Abnormality of the aorta (present) Family history: yes
Pathogenic (Feb 25, 2020)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Hypertrichotic osteochondrodysplasia Cantu type (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001429923.1 First in ClinVar: Aug 21, 2020 Last updated: Aug 21, 2020	Clinical Features: Hirsutism (present) , Protuberant abdomen (present) , Patent foramen ovale (present) , Micrognathia (present) , Macroglossia (present) , Hyperplastic labia majora (present) , Patent ductus … (more) Hirsutism (present) , Protuberant abdomen (present) , Patent foramen ovale (present) , Micrognathia (present) , Macroglossia (present) , Hyperplastic labia majora (present) , Patent ductus arteriosus (present) , Narrow chest (present) , Dolichocephaly (present) , Large for gestational age (present) , Umbilical hernia (present) , Muscular ventricular septal defect (present) , Short neck (present) , Prominent forehead (present) (less) Sex: female Tissue: blood
Pathogenic (Aug 30, 2019)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Hypertrichotic osteochondrodysplasia Cantu type Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV001451475.1 First in ClinVar: Dec 22, 2020 Last updated: Dec 22, 2020	Publications: PubMed (3) PubMed: 22608503‚ 22610116‚ 26871653 Comment: 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 … (more) 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. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrichotic osteochondrodysplasia Cantu type (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Suma Genomics Accession: SCV001837611.1 First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021
Pathogenic (Feb 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018662.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199095.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jun 08, 2012)	no assertion criteria provided Method: literature only	HYPERTRICHOTIC OSTEOCHONDRODYSPLASIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000050490.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 22608503‚ 22610116 Comment on evidence: In 3 unrelated patients with hypertrichotic osteochondrodysplasia (Cantu syndrome; 239850), van Bon et al. (2012) identified heterozygosity for a de novo 3460C-T transition in exon … (more) In 3 unrelated patients with hypertrichotic osteochondrodysplasia (Cantu syndrome; 239850), van Bon et al. (2012) identified heterozygosity for a de novo 3460C-T transition in exon 27 of the ABCC9 gene, resulting in an arg1154-to-trp (R1154W) substitution at a highly conserved residue in the second type 1 transmembrane domain (TMD2). The mutation was not found in any of the over 5,000 publicly available exomes. In a 5.5-year-old girl with Cantu syndrome, Harakalova et al. (2012) identified heterozygosity for a de novo R1154W mutation in ABCC9. The patient displayed the characteristic facies and generalized hypertrichosis of Cantu syndrome, associated with deep palmar/plantar creases, soft skin, a silvery shine to her hair, patent ductus arteriosus and foramen ovale, and a left ventricle that was at the upper limit of normal in size. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927352.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954099.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
De Novo Mutation in ABCC9 Causes Hypertrichosis Acromegaloid Facial Features Disorder.	Afifi HH	Pediatric dermatology	2016	PMID: 26871653
Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy.	Bottillo I	Gene	2016	PMID: 26656175
A genome sequencing program for novel undiagnosed diseases.	Bloss CS	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25790160
Wide clinical variability in conditions with coarse facial features and hypertrichosis caused by mutations in ABCC9.	Czeschik JC	American journal of medical genetics. Part A	2013	PMID: 23307537
Dominant missense mutations in ABCC9 cause Cantú syndrome.	Harakalova M	Nature genetics	2012	PMID: 22610116
Cantú syndrome is caused by mutations in ABCC9.	van Bon BW	American journal of human genetics	2012	PMID: 22608503

Text-mined citations for rs387907208 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387907208 ...