PM2, PM3_Strong
ClinVar Genomic variation as it relates to human health
NM_001171.6(ABCC6):c.742C>T (p.Leu248Phe)
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.
(7)
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.
Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(3)
Likely pathogenic(2); Uncertain significance(3)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001171.6(ABCC6):c.742C>T (p.Leu248Phe)
Variation ID: 281270 Accession: VCV000281270.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.11 16: 16208780 (GRCh38) [ NCBI UCSC ] 16: 16302637 (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 Dec 6, 2016 Nov 24, 2024 Mar 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001171.6:c.742C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001162.5:p.Leu248Phe missense NM_001351800.1:c.400C>T NP_001338729.1:p.Leu134Phe missense NR_147784.1:n.779C>T non-coding transcript variant NC_000016.10:g.16208780G>A NC_000016.9:g.16302637G>A NG_007558.3:g.19838C>T LRG_1115:g.19838C>T LRG_1115t1:c.742C>T LRG_1115p1:p.Leu248Phe - Protein change
- L248F, L134F
- Other names
-
p.Leu248Phe
- Canonical SPDI
- NC_000016.10:16208779:G:A
-
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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0.00120 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00070
The Genome Aggregation Database (gnomAD), exomes 0.00080
1000 Genomes Project 0.00120
1000 Genomes Project 30x 0.00125
Trans-Omics for Precision Medicine (TOPMed) 0.00200
The Genome Aggregation Database (gnomAD) 0.00214
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00239
- 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 |
1473 | 1836 | |
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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000300804.15 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
May 28, 2019 | RCV000499195.4 | |
|
ABCC6-related disorder
|
Likely pathogenic (2) |
criteria provided, single submitter
|
Aug 30, 2022 | RCV002291274.4 |
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
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jan 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331967.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 5
Sex: mixed
|
|
|
Likely pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive inherited pseudoxanthoma elasticum
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139968.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely pathogenic
(Aug 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
ABCC6-related disorder
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002583667.1
First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022 |
Comment:
PM2, PM3_Strong
|
|
|
Uncertain significance
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004141230.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
|
Uncertain significance
(Oct 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005411259.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
BS1, PM3
Number of individuals with the variant: 2
|
|
|
Uncertain significance
(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: SCV000588933.2
First in ClinVar: Oct 27, 2017 Last updated: Mar 07, 2021 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Angioid streaks (present)
Tissue: blood
Method: sanger sequencing
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Angioid streaks (present)
Tissue: blood
Method: sanger sequencing
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Papule (present)
Tissue: blood
Method: sanger sequencing
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Weak or absent arterial pulse (present) , Angina pectoris (present) , Abnormal EKG (present)
Tissue: blood
Method: sanger sequencing
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Angioid streaks (present) , Vascular surgery (present)
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) , Angina pectoris (present) , Abnormal EKG (present)
Tissue: blood
Method: sanger sequencing
Observation 7:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Angina pectoris (present) , Abnormal EKG (present)
Tissue: blood
Method: sanger sequencing
Observation 8:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present)
Tissue: blood
Method: sanger sequencing
|
|
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Uncertain significance
(Jun 04, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ABCC6-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005351994.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ABCC6 c.742C>T variant is predicted to result in the amino acid substitution p.Leu248Phe. This variant has been reported in a family with pseudoxanthoma elasticum … (more)
The ABCC6 c.742C>T variant is predicted to result in the amino acid substitution p.Leu248Phe. This variant has been reported in a family with pseudoxanthoma elasticum (Miksch et al. 2005. PubMed ID: 16086317). This variant has also been reported with uncertain significance in an individual with a retinal disorder (Table S12 in Diñeiro et al. 2020. PubMed ID: 32483926). This variant has been reported in the compound heterozygous state in an individual with an ectopic mineralization disorder (Table S1 in Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.53% of alleles in individuals of African descent in gnomAD v2 (as displayed in the table above). However, in gnomAD v4 (available only on GRCh38), this variant is reported in 0.57% of alleles in a subpopulation, including 3 homozygotes. This population data is not consistent with this variant being a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
Comment:
Comment:
BS1, PM3
Comment:
The ABCC6 c.742C>T variant is predicted to result in the amino acid substitution p.Leu248Phe. This variant has been reported in a family with pseudoxanthoma elasticum (Miksch et al. 2005. PubMed ID: 16086317). This variant has also been reported with uncertain significance in an individual with a retinal disorder (Table S12 in Diñeiro et al. 2020. PubMed ID: 32483926). This variant has been reported in the compound heterozygous state in an individual with an ectopic mineralization disorder (Table S1 in Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.53% of alleles in individuals of African descent in gnomAD v2 (as displayed in the table above). However, in gnomAD v4 (available only on GRCh38), this variant is reported in 0.57% of alleles in a subpopulation, including 3 homozygotes. This population data is not consistent with this variant being a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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:
PM2, PM3_Strong
Comment:
BS1, PM3
Comment:
The ABCC6 c.742C>T variant is predicted to result in the amino acid substitution p.Leu248Phe. This variant has been reported in a family with pseudoxanthoma elasticum (Miksch et al. 2005. PubMed ID: 16086317). This variant has also been reported with uncertain significance in an individual with a retinal disorder (Table S12 in Diñeiro et al. 2020. PubMed ID: 32483926). This variant has been reported in the compound heterozygous state in an individual with an ectopic mineralization disorder (Table S1 in Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.53% of alleles in individuals of African descent in gnomAD v2 (as displayed in the table above). However, in gnomAD v4 (available only on GRCh38), this variant is reported in 0.57% of alleles in a subpopulation, including 3 homozygotes. This population data is not consistent with this variant being a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort. | Saeidian AH | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906475 |
| 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 |
| Comprehensive genomic diagnosis of inherited retinal and optical nerve disorders reveals hidden syndromes and personalized therapeutic options. | Diñeiro M | Acta ophthalmologica | 2020 | PMID: 32483926 |
| Mutation spectrum in the ABCC6 gene and genotype-phenotype correlations in a French cohort with pseudoxanthoma elasticum. | Legrand A | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28102862 |
| Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. | Miksch S | Human mutation | 2005 | PMID: 16086317 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCC6 | - | - | - | - |
Text-mined citations for rs72653756 ...
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 Nov 25, 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.