ClinVar Genomic variation as it relates to human health
NM_001171.6(ABCC6):c.4015C>T (p.Arg1339Cys)
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.4015C>T (p.Arg1339Cys)
Variation ID: 6576 Accession: VCV000006576.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.11 16: 16154899 (GRCh38) [ NCBI UCSC ] 16: 16248756 (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 Aug 21, 2017 Feb 14, 2024 Sep 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001171.6:c.4015C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001162.5:p.Arg1339Cys missense NM_001351800.1:c.3673C>T NP_001338729.1:p.Arg1225Cys missense NR_147784.1:n.3677C>T non-coding transcript variant NC_000016.10:g.16154899G>A NC_000016.9:g.16248756G>A NG_007558.3:g.73719C>T LRG_1115:g.73719C>T LRG_1115t1:c.4015C>T LRG_1115p1:p.Arg1339Cys O95255:p.Arg1339Cys - Protein change
- R1339C, R1225C
- Other names
- -
- Canonical SPDI
- NC_000016.10:16154898:G:A
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00008
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 | ||
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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. |
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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
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. |
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Pathogenic (2) |
no assertion criteria provided
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Mar 1, 2021 | RCV000006954.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2023 | RCV001781196.7 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jan 11, 2023 | RCV002509146.1 |
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. |
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Pathogenic
(Sep 07, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002020519.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 06, 2023)
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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: SCV002245911.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1339 of the ABCC6 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1339 of the ABCC6 protein (p.Arg1339Cys). This variant is present in population databases (rs28939702, gnomAD 0.02%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 10954200, 12384774). ClinVar contains an entry for this variant (Variation ID: 6576). 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. Experimental studies have shown that this missense change affects ABCC6 function (PMID: 24352041, 27994049). 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, 18157818). 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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Pathogenic
(Jun 15, 2018)
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no assertion criteria provided
Method: literature only
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PSEUDOXANTHOMA ELASTICUM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027150.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 18, 2018 |
Comment on evidence:
In 17 Afrikaner families in South Africa with autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2002) found that 53% of the PXE-associated … (more)
In 17 Afrikaner families in South Africa with autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2002) found that 53% of the PXE-associated alleles of the ABCC6 gene had a 4015C-T transition, which caused an arg1339-to-cys (R1339C) mutation. Haplotype analysis showed that the mutation was identical by descent in these families. (less)
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Pathogenic
(Mar 01, 2021)
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no assertion criteria provided
Method: research
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Autosomal recessive inherited pseudoxanthoma elasticum
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
PXE International
Accession: SCV000589099.2
First in ClinVar: Aug 21, 2017 Last updated: Mar 07, 2021 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Papule (present)
Tissue: blood
Method: sanger sequencing
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Malignant tumor of prostate (present) , Papule (present) , Skin plaque (present) , Retinal hemorrhage (present)
Tissue: blood
Method: sanger sequencing
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Papule (present)
Tissue: blood
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Retinal hemorrhage (present)
Tissue: blood
Method: sanger sequencing
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Asymptomatic peripheral arterial disease of the lower limbs (present) , Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Weak or absent arterial … (more)
Asymptomatic peripheral arterial disease of the lower limbs (present) , Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Weak or absent arterial pulse (present) (less)
Tissue: blood
Method: sanger sequencing
Observation 6:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Weak or absent arterial pulse (present)
Age: 20-29 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 7:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Weak or absent arterial pulse (present)
Age: 30-39 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 8:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Weak or absent arterial pulse (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 9:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Weak or absent arterial pulse (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 10:
Number of individuals with the variant: 1
Clinical Features:
Papule (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 11:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Intermittent claudication (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 12:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Intermittent claudication (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 13:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Intermittent claudication (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 14:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Gastrointestinal hemorrhage (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 15:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Gastrointestinal hemorrhage (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 16:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 17:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 18:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Gastrointestinal hemorrhage (present) , Vascular surgery (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 19:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Angioid streaks (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 20:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Intermittent claudication (present)
Age: 50-59 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 21:
Number of individuals with the variant: 1
Clinical Features:
Retinal hemorrhage (present)
Age: 50-59 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 22:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Intermittent claudication (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 23:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 24:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 25:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Weak or absent arterial pulse (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 26:
Number of individuals with the variant: 1
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 27:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Intermittent claudication (present) , Myocardial infarction (present)
Age: 40-49 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 28:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Intermittent claudication (present) , Myocardial infarction (present)
Age: 40-49 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 29:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Angioid streaks (present) , Weak or absent arterial pulse (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 30-39 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 30:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Angioid streaks (present)
Age: 10-19 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 31:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present)
Age: 20-29 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 32:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present)
Age: 20-29 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 33:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Angioid streaks (present) , Intermittent claudication (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 20-29 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 34:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Intermittent claudication (present)
Age: 50-59 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 35:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Weak or absent arterial pulse (present)
Age: 20-29 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 36:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Intermittent claudication (present)
Age: 60-69 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 37:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Intermittent claudication (present)
Age: 60-69 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 38:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Angioid streaks (present)
Age: 10-19 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 39:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Weak or absent arterial pulse (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 40:
Number of individuals with the variant: 1
Clinical Features:
Papule (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 41:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Angioid streaks (present) , Vascular surgery (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 42:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Angioid streaks (present) , Vascular surgery (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 43:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Angioid streaks (present) , Intermittent claudication (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 44:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Peau d'orange retinal changes (present) , Intermittent claudication (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 0-9 years
Ethnicity/Population group: African American
Tissue: blood
Method: sanger sequencing
Observation 45:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Retinal hemorrhage (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 46:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 47:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present)
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 48:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 49:
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: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
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Likely pathogenic
(Jan 11, 2023)
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no assertion criteria provided
Method: clinical testing
|
Low-set, posteriorly rotated ears
Affected status: yes
Allele origin:
germline
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PG23_Medical Genetics Lab, ASST Papa Giovanni XXIII
Accession: SCV002819144.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
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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 |
Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo; pharmacological correction of the mislocalized proteins. | Pomozi V | The Journal of investigative dermatology | 2014 | PMID: 24352041 |
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 |
Serum factors from pseudoxanthoma elasticum patients alter elastic fiber formation in vitro. | Le Saux O | The Journal of investigative dermatology | 2006 | PMID: 16543900 |
Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. | Miksch S | Human mutation | 2005 | PMID: 16086317 |
Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa. | Le Saux O | Human genetics | 2002 | PMID: 12384774 |
Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum. | Struk B | Journal of molecular medicine (Berlin, Germany) | 2000 | PMID: 10954200 |
Text-mined citations for rs28939702 ...
HelpRecord last updated Mar 17, 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.