This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1302 of the ABCC6 protein (p.Gly1302Arg). This variant is present in population databases (rs63749856, gnomAD 0.01%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 11536079, 16086317, 21179111). ClinVar contains an entry for this variant (Variation ID: 6579). 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%. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001171.6(ABCC6):c.3904G>A (p.Gly1302Arg)
Germline
Classification
Help
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.
(9)
Help
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001171.6(ABCC6):c.3904G>A (p.Gly1302Arg)
Variation ID: 6579 Accession: VCV000006579.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.11 16: 16155010 (GRCh38) [ NCBI UCSC ] 16: 16248867 (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 Oct 9, 2016 Oct 8, 2024 Aug 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001171.6:c.3904G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001162.5:p.Gly1302Arg missense NM_001351800.1:c.3562G>A NP_001338729.1:p.Gly1188Arg missense NR_147784.1:n.3566G>A non-coding transcript variant NC_000016.10:g.16155010C>T NC_000016.9:g.16248867C>T NG_007558.3:g.73608G>A LRG_1115:g.73608G>A LRG_1115t1:c.3904G>A LRG_1115p1:p.Gly1302Arg O95255:p.Gly1302Arg - Protein change
- G1302R, G1188R
- Other names
- -
- Canonical SPDI
- NC_000016.10:16155009:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ABCC6 | - | - |
GRCh38 GRCh38 GRCh37 |
1474 | 1837 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, single submitter
|
Apr 4, 2024 | RCV000006957.11 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 31, 2024 | RCV000255838.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 14, 2022 | RCV000762958.3 | |
|
ABCC6-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 26, 2024 | RCV004737139.1 |
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
(Mar 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pseudoxanthoma elasticum, forme fruste
Autosomal recessive inherited pseudoxanthoma elasticum Arterial calcification, generalized, of infancy, 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893396.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023918.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002204985.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1302 of the ABCC6 protein (p.Gly1302Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1302 of the ABCC6 protein (p.Gly1302Arg). This variant is present in population databases (rs63749856, gnomAD 0.01%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 11536079, 16086317, 21179111). ClinVar contains an entry for this variant (Variation ID: 6579). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321368.11
First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate that this variant, located at a position within an ATP binding region of the ABC transporter 2 domain, disrupts the ABCC6-mediated … (more)
Published functional studies demonstrate that this variant, located at a position within an ATP binding region of the ABC transporter 2 domain, disrupts the ABCC6-mediated transport of glutathione conjugates (PMID: 11880368); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19133228, 19339160, 16086317, 12673275, 17617515, 32873932, 17251343, 20189652, 32413269, 21179111, 11880368, 29480367, 15727254, 34205333, 11536079, 34906475) (less)
|
|
|
Pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive inherited pseudoxanthoma elasticum
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809525.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
|
Pathogenic
(Oct 01, 2002)
|
no assertion criteria provided
Method: literature only
|
PSEUDOXANTHOMA ELASTICUM
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027153.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 18, 2018 |
Comment on evidence:
In a cohort of 122 unrelated patients with pseudoxanthoma elasticum (PXE; 264800) from several countries, Le Saux et al. (2001) found a 3904G-A transition in … (more)
In a cohort of 122 unrelated patients with pseudoxanthoma elasticum (PXE; 264800) from several countries, Le Saux et al. (2001) found a 3904G-A transition in exon 28 of the ABCC6 gene that resulted in a gly1302-to-arg (G1302R) amino acid substitution in the second intracellular nucleotide-binding domain. The mutation, present in homozygosity, occurred in a total of 4 alleles from patients from the United States, giving an allele frequency of 5.4% in a total of 74 United States alleles. It was not found in the European population. Ilias et al. (2002) showed that the G1302R mutation did not affect the expression of the ABCC6 protein in infected insect cells, but that the protein was essentially inactive in the MgATP-dependent transport of N-ethylmaleimide S-glutathione (NEM-GS) or leukotriene-C4. (less)
|
|
|
Pathogenic
(Sep 26, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ABCC6-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005350309.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ABCC6 c.3904G>A variant is predicted to result in the amino acid substitution p.Gly1302Arg. This variant has been reported in the homozygous and compound heterozygous … (more)
The ABCC6 c.3904G>A variant is predicted to result in the amino acid substitution p.Gly1302Arg. This variant has been reported in the homozygous and compound heterozygous states in individuals with pseudoxanthoma elasticum (Le Saux et al. 2001. PubMed ID: 11536079; Miksch et al. 2005. PubMed ID: 16086317; Li et al. 2011. PubMed ID: 21179111; Table S1, Boraldi et al. 2021. PubMed ID: 34205333). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Mar 01, 2021)
|
no assertion criteria provided
Method: research
|
Autosomal recessive inherited pseudoxanthoma elasticum
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
PXE International
Accession: SCV000589086.2
First in ClinVar: Aug 21, 2017 Last updated: Mar 07, 2021 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Retinal hemorrhage (present) , Intermittent claudication (present) , Angina pectoris (present) , Abnormal EKG (present)
Tissue: blood
Method: sanger sequencing
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Retinal hemorrhage (present) , Intermittent claudication (present) , Angina pectoris (present) , Abnormal EKG (present)
Tissue: blood
Method: sanger sequencing
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Retinal hemorrhage (present) , Weak or absent arterial pulse (present)
Tissue: blood
Method: sanger sequencing
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Retinal hemorrhage (present) , Weak or absent arterial pulse (present)
Tissue: blood
Method: sanger sequencing
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Retinal hemorrhage (present) , Intermittent claudication (present)
Age: 60-69 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 6:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Intermittent claudication (present)
Age: 30-39 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)
Age: 20-29 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 8:
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: Causasians
Tissue: blood
Method: sanger sequencing
Observation 9:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Retinal hemorrhage (present)
Age: 50-59 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 10:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Intermittent claudication (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 30-39 years
Ethnicity/Population group: Causasians
Tissue: blood
Method: sanger sequencing
Observation 11:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Intermittent claudication (present) , Angina pectoris (present) , Abnormal EKG (present)
Age: 30-39 years
Ethnicity/Population group: Causasians
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)
Age: 70-79 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 13:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Autosomal recessive inherited pseudoxanthoma elasticum
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV000607216.1
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
|
Comment:
Comment:
Published functional studies demonstrate that this variant, located at a position within an ATP binding region of the ABC transporter 2 domain, disrupts the ABCC6-mediated transport of glutathione conjugates (PMID: 11880368); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19133228, 19339160, 16086317, 12673275, 17617515, 32873932, 17251343, 20189652, 32413269, 21179111, 11880368, 29480367, 15727254, 34205333, 11536079, 34906475)
Comment:
The ABCC6 c.3904G>A variant is predicted to result in the amino acid substitution p.Gly1302Arg. This variant has been reported in the homozygous and compound heterozygous states in individuals with pseudoxanthoma elasticum (Le Saux et al. 2001. PubMed ID: 11536079; Miksch et al. 2005. PubMed ID: 16086317; Li et al. 2011. PubMed ID: 21179111; Table S1, Boraldi et al. 2021. PubMed ID: 34205333). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
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 significance of the variant.
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:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1302 of the ABCC6 protein (p.Gly1302Arg). This variant is present in population databases (rs63749856, gnomAD 0.01%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 11536079, 16086317, 21179111). ClinVar contains an entry for this variant (Variation ID: 6579). 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%. For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies demonstrate that this variant, located at a position within an ATP binding region of the ABC transporter 2 domain, disrupts the ABCC6-mediated transport of glutathione conjugates (PMID: 11880368); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19133228, 19339160, 16086317, 12673275, 17617515, 32873932, 17251343, 20189652, 32413269, 21179111, 11880368, 29480367, 15727254, 34205333, 11536079, 34906475)
Comment:
The ABCC6 c.3904G>A variant is predicted to result in the amino acid substitution p.Gly1302Arg. This variant has been reported in the homozygous and compound heterozygous states in individuals with pseudoxanthoma elasticum (Le Saux et al. 2001. PubMed ID: 11536079; Miksch et al. 2005. PubMed ID: 16086317; Li et al. 2011. PubMed ID: 21179111; Table S1, Boraldi et al. 2021. PubMed ID: 34205333). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
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 significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Angioid streaks in Pseudoxanthoma Elasticum: role of the p.R1268Q mutation in the ABCC6 gene. | Li Q | The Journal of investigative dermatology | 2011 | PMID: 21179111 |
| 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 |
| Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). | Iliás A | The Journal of biological chemistry | 2002 | PMID: 11880368 |
| A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum. | Le Saux O | American journal of human genetics | 2001 | PMID: 11536079 |
Text-mined citations for rs63749856 ...
HelpThese 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 Oct 13, 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.