ClinVar Genomic variation as it relates to human health
NM_001171.6(ABCC6):c.4016G>A (p.Arg1339His)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001171.6(ABCC6):c.4016G>A (p.Arg1339His)
Variation ID: 265021 Accession: VCV000265021.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.11 16: 16154898 (GRCh38) [ NCBI UCSC ] 16: 16248755 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 10, 2016 Feb 14, 2024 Jan 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001171.6:c.4016G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001162.5:p.Arg1339His missense NM_001351800.1:c.3674G>A NP_001338729.1:p.Arg1225His missense NR_147784.1:n.3678G>A non-coding transcript variant NC_000016.10:g.16154898C>T NC_000016.9:g.16248755C>T NG_007558.3:g.73720G>A LRG_1115:g.73720G>A LRG_1115t1:c.4016G>A LRG_1115p1:p.Arg1339His O95255:p.Arg1339His - Protein change
- R1339H, R1225H
- Other names
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- Canonical SPDI
- NC_000016.10:16154897:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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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. |
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ABCC6 | - | - |
GRCh38 GRCh38 GRCh37 |
1441 | 1798 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 12, 2024 | RCV000255253.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2021 | RCV000499080.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 17, 2021 | RCV002500955.1 |
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
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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. |
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Likely pathogenic
(Mar 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321370.6
First in ClinVar: Oct 10, 2016 Last updated: Oct 10, 2016 |
Comment:
The R1339H variant in the ABCC6 gene has been reported at least seven times previously in association with PXE (Miksch et al., 2005, Pfendner et … (more)
The R1339H variant in the ABCC6 gene has been reported at least seven times previously in association with PXE (Miksch et al., 2005, Pfendner et al. 2007, Vanakker et al., 2008). The R1339H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1339H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species In silico analysis predicts this variant is probably damaging to the protein structure/function as it occurs in the highly conserved second ATP binding domain required for proper gene function and in which numerous pathogenic variants are clustered. Missense variants at the same residue (R1339C, R1339L) and in nearby residues (L1335P, L1335Q, I1342T) have been reported in the Human Gene Mutation Database in association with PXE (Stenson et al., 2014), supporting the functional importance of this region of the protein. According to the ACMG Guidelines this variant is classified as likely pathogenic; however, the unlikely possibility that it is benign cannot be excluded. (less)
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Pathogenic
(Mar 01, 2021)
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criteria provided, single submitter
Method: research
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Autosomal recessive inherited pseudoxanthoma elasticum
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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PXE International
Accession: SCV000589101.2
First in ClinVar: Oct 27, 2017 Last updated: Mar 07, 2021 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Gastrointestinal hemorrhage (present) , Intermittent claudication (present) , Angina pectoris (present) , Abnormal EKG … (more)
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Gastrointestinal hemorrhage (present) , Intermittent claudication (present) , Angina pectoris (present) , Abnormal EKG (present) (less)
Age: 40-49 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Weak or absent arterial pulse (present)
Age: 50-59 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
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Pathogenic
(Nov 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pseudoxanthoma elasticum, forme fruste
Autosomal recessive inherited pseudoxanthoma elasticum Arterial calcification, generalized, of infancy, 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809862.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002242901.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1339 of the ABCC6 protein (p.Arg1339His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1339 of the ABCC6 protein (p.Arg1339His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 16086317, 18157818). This variant is also known as p.R1339Q. ClinVar contains an entry for this variant (Variation ID: 265021). 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 ABCC6 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1339 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16086317, 19339160, 27994049). 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)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Reassessment of causality of ABCC6 missense variants associated with pseudoxanthoma elasticum based on Sherloc. | Verschuere S | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32873932 |
Stabilization of Nucleotide Binding Domain Dimers Rescues ABCC6 Mutants Associated with Pseudoxanthoma Elasticum. | Ran Y | The Journal of biological chemistry | 2017 | PMID: 27994049 |
Spectrum of genetic variation at the ABCC6 locus in South Africans: Pseudoxanthoma elasticum patients and healthy individuals. | Ramsay M | Journal of dermatological science | 2009 | PMID: 19339160 |
Novel clinico-molecular insights in pseudoxanthoma elasticum provide an efficient molecular screening method and a comprehensive diagnostic flowchart. | Vanakker OM | Human mutation | 2008 | PMID: 18157818 |
Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum. | Pfendner EG | Journal of medical genetics | 2007 | PMID: 17617515 |
Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. | Miksch S | Human mutation | 2005 | PMID: 16086317 |
Text-mined citations for rs63750622 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.