ClinVar Genomic variation as it relates to human health
NM_001171.6(ABCC6):c.1552C>T (p.Arg518Ter)
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.1552C>T (p.Arg518Ter)
Variation ID: 30339 Accession: VCV000030339.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.11 16: 16190247 (GRCh38) [ NCBI UCSC ] 16: 16284104 (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 Sep 29, 2015 Apr 15, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001171.6:c.1552C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001162.5:p.Arg518Ter nonsense NM_001351800.1:c.1210C>T NP_001338729.1:p.Arg404Ter nonsense NR_147784.1:n.1589C>T non-coding transcript variant NC_000016.10:g.16190247G>A NC_000016.9:g.16284104G>A NG_007558.3:g.38371C>T LRG_1115:g.38371C>T LRG_1115t1:c.1552C>T LRG_1115p1:p.Arg518Ter - Protein change
- R518*, R404*
- Other names
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- Canonical SPDI
- NC_000016.10:16190246: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (4) |
criteria provided, single submitter
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Sep 1, 2022 | RCV000023280.9 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 23, 2019 | RCV000023279.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 1, 2014 | RCV000191057.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 24, 2023 | RCV000429924.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2022 | RCV002477007.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 6, 2022 | RCV003415731.4 |
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
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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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Pathogenic
(Apr 01, 2014)
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criteria provided, single submitter
Method: clinical testing
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Pseudoxanthoma elasticum, forme fruste
Pseudoxanthoma elasticum (Autosomal unknown)
Affected status: yes
Allele origin:
paternal
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Baylor Genetics
Study: Adult_WES
Accession: SCV000245446.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment:
This variant has been previously reported as disease-causing and was found once in our laboratory in a 39-year-old male with hereditary anemia, angioid streaks on … (more)
This variant has been previously reported as disease-causing and was found once in our laboratory in a 39-year-old male with hereditary anemia, angioid streaks on retina, possible pseudoxanthoma elasticum, fatigue, chronic joint pain. Variant was in trans with a common missense variant [c.793A>G (p.R265G)]. (less)
Number of individuals with the variant: 1
Age: 30-39 years
Sex: male
Ethnicity/Population group: Causasians
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Pathogenic
(Jul 09, 2018)
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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: SCV000516089.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019 |
Comment:
The p.R518X nonsense variant in the ABCC6 gene has been reported previously in association with PXE (Meloni et al., 2001). This variant is predicted to … (more)
The p.R518X nonsense variant in the ABCC6 gene has been reported previously in association with PXE (Meloni et al., 2001). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret this variant as pathogenic. (less)
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Pathogenic
(Aug 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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Arterial calcification, generalized, of infancy, 2
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366804.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive inherited pseudoxanthoma elasticum
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573157.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000030339/ PMID: 11439001). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Angioid streaks of the fundus (present) , Premature skin wrinkling (present) , Yellow papule (present) , Redundant neck skin (present)
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Pathogenic
(Mar 11, 2022)
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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: SCV002793157.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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ABCC6-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004109288.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ABCC6 c.1552C>T variant is predicted to result in premature protein termination (p.Arg518*). This variant has been reported in an individual with autosomal recessive pseudoxanthoma … (more)
The ABCC6 c.1552C>T variant is predicted to result in premature protein termination (p.Arg518*). This variant has been reported in an individual with autosomal recessive pseudoxanthoma elasticum (PXE) and autosomal recessive generalized calcification of infancy (GACI) (Table 1, Meloni et al. 2001. PubMed ID: 11439001; Table 1, Miksch et al. 2005. PubMed ID: 16086317; Table 2, Pfendner et al. 2007. PubMed ID: 17617515; Table 2, Nitschke et al. 2011. PubMed ID: 22209248; Table S1, Boraldi et al. 2021. PubMed ID: 34205333; Table S1, Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16284104-G-A). Nonsense variants in ABCC6 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747147.14
First in ClinVar: Jul 10, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 24, 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: SCV002245561.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg518*) in the ABCC6 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg518*) in the ABCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC6 are known to be pathogenic (PMID: 11536079, 17617515). This variant is present in population databases (rs72650700, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 11439001). ClinVar contains an entry for this variant (Variation ID: 30339). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Autosomal recessive inherited pseudoxanthoma elasticum
Affected status: yes
Allele origin:
germline
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PXE International
Accession: SCV000588966.1
First in ClinVar: Aug 21, 2017 Last updated: Aug 21, 2017 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks of the retina (present)
Tissue: blood
Method: sanger sequencing
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angina pectoris (present) , Abnormal EKG (present)
Tissue: blood
Method: sanger sequencing
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Angioid streaks of the retina (present)
Tissue: blood
Method: sanger sequencing
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present)
Tissue: blood
Method: sanger sequencing
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks of the retina (present)
Tissue: blood
Method: sanger sequencing
Observation 6:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks of the retina (present)
Tissue: blood
Method: sanger sequencing
Observation 7:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Angina pectoris (present) , Abnormal EKG (present)
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) , Intermittent claudication (present)
Age: 40-49 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 9:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Intermittent claudication (present)
Age: 20-29 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 10:
Number of individuals with the variant: 1
Age: 0-9 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
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Pathogenic
(Jan 13, 2012)
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no assertion criteria provided
Method: literature only
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ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044570.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Generalized Arterial Calcification of Infancy 2 In a 3-year-old Spanish boy with generalized arterial calcification of infancy (GACI2; 614473), who had calcification of the splenic … (more)
Generalized Arterial Calcification of Infancy 2 In a 3-year-old Spanish boy with generalized arterial calcification of infancy (GACI2; 614473), who had calcification of the splenic and pancreatic arteries, nephrocalcinosis, severe hypertension, cardiomegaly, psychomotor retardation, and abdominal distention, Nitschke et al. (2012) identified compound heterozygosity for 2 mutations in the ABCC6 gene: an R1141X substitution (603234.0001) and a 1552C-T transition in exon 12, resulting in an arg518-to-ter (R518X) substitution. Pseudoxanthoma Elasticum The R518X mutation has been identified in compound heterozygosity with another ABCC6 mutation in patients with pseudoxanthoma elasticum (PXE; 264800) (see, e.g., Meloni et al., 2001 and Miksch et al., 2005). (less)
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Pathogenic
(Jan 13, 2012)
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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: SCV000044571.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Generalized Arterial Calcification of Infancy 2 In a 3-year-old Spanish boy with generalized arterial calcification of infancy (GACI2; 614473), who had calcification of the splenic … (more)
Generalized Arterial Calcification of Infancy 2 In a 3-year-old Spanish boy with generalized arterial calcification of infancy (GACI2; 614473), who had calcification of the splenic and pancreatic arteries, nephrocalcinosis, severe hypertension, cardiomegaly, psychomotor retardation, and abdominal distention, Nitschke et al. (2012) identified compound heterozygosity for 2 mutations in the ABCC6 gene: an R1141X substitution (603234.0001) and a 1552C-T transition in exon 12, resulting in an arg518-to-ter (R518X) substitution. Pseudoxanthoma Elasticum The R518X mutation has been identified in compound heterozygosity with another ABCC6 mutation in patients with pseudoxanthoma elasticum (PXE; 264800) (see, e.g., Meloni et al., 2001 and Miksch et al., 2005). (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Autosomal recessive inherited pseudoxanthoma elasticum
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000607215.1
First in ClinVar: Oct 14, 2017 Last updated: Oct 14, 2017 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of the retina (present) , Abnormality of eye movement (present) , Conductive hearing impairment (present) , Short attention span (present) , Depression (present) , … (more)
Abnormality of the retina (present) , Abnormality of eye movement (present) , Conductive hearing impairment (present) , Short attention span (present) , Depression (present) , Anxiety (present) , Autistic behavior (present) , Epidermal thickening (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-05-10
Testing laboratory interpretation: Pathogenic
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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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Molecular diagnostic experience of whole-exome sequencing in adult patients. | Posey JE | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633545 |
Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. | Nitschke Y | American journal of human genetics | 2012 | PMID: 22209248 |
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 |
A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum. | Le Saux O | American journal of human genetics | 2001 | PMID: 11536079 |
Pseudoxanthoma elasticum: Point mutations in the ABCC6 gene and a large deletion including also ABCC1 and MYH11. | Meloni I | Human mutation | 2001 | PMID: 11439001 |
Text-mined citations for rs72650700 ...
HelpRecord last updated Apr 15, 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.