In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant has not been reported in the literature in individuals with DTNA-related disease. ClinVar contains an entry for this variant (Variation ID: 411865). This variant is present in population databases (rs774912781, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces arginine with histidine at codon 80 of the DTNA protein (p.Arg80His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.
ClinVar Genomic variation as it relates to human health
NM_001386795.1(DTNA):c.239G>A (p.Arg80His)
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.
(2)
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.
Uncertain significance
2
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001386795.1(DTNA):c.239G>A (p.Arg80His)
Variation ID: 411865 Accession: VCV000411865.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 34794127 (GRCh38) [ NCBI UCSC ] 18: 32374091 (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 May 26, 2018 Feb 20, 2024 Mar 7, 2021 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001386795.1:c.239G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001373724.1:p.Arg80His missense NM_001128175.2:c.239G>A NP_001121647.1:p.Arg80His missense NM_001198938.2:c.239G>A NP_001185867.1:p.Arg80His missense NM_001198939.2:c.239G>A NP_001185868.1:p.Arg80His missense NM_001198940.2:c.239G>A NP_001185869.1:p.Arg80His missense NM_001198941.2:c.239G>A NP_001185870.1:p.Arg80His missense NM_001198945.2:c.239G>A NP_001185874.1:p.Arg80His missense NM_001386753.1:c.239G>A NP_001373682.1:p.Arg80His missense NM_001386754.1:c.239G>A NP_001373683.1:p.Arg80His missense NM_001386755.1:c.239G>A NP_001373684.1:p.Arg80His missense NM_001386756.1:c.239G>A NP_001373685.1:p.Arg80His missense NM_001386757.1:c.239G>A NP_001373686.1:p.Arg80His missense NM_001386758.1:c.239G>A NP_001373687.1:p.Arg80His missense NM_001386759.1:c.239G>A NP_001373688.1:p.Arg80His missense NM_001386760.1:c.239G>A NP_001373689.1:p.Arg80His missense NM_001386761.1:c.239G>A NP_001373690.1:p.Arg80His missense NM_001386762.1:c.239G>A NP_001373691.1:p.Arg80His missense NM_001386763.1:c.239G>A NP_001373692.1:p.Arg80His missense NM_001386764.1:c.239G>A NP_001373693.1:p.Arg80His missense NM_001386765.1:c.239G>A NP_001373694.1:p.Arg80His missense NM_001386766.1:c.239G>A NP_001373695.1:p.Arg80His missense NM_001386767.1:c.239G>A NP_001373696.1:p.Arg80His missense NM_001386768.1:c.239G>A NP_001373697.1:p.Arg80His missense NM_001386769.1:c.239G>A NP_001373698.1:p.Arg80His missense NM_001386770.1:c.239G>A NP_001373699.1:p.Arg80His missense NM_001386771.1:c.239G>A NP_001373700.1:p.Arg80His missense NM_001386772.1:c.239G>A NP_001373701.1:p.Arg80His missense NM_001386773.1:c.239G>A NP_001373702.1:p.Arg80His missense NM_001386774.1:c.239G>A NP_001373703.1:p.Arg80His missense NM_001386775.1:c.239G>A NP_001373704.1:p.Arg80His missense NM_001386776.1:c.239G>A NP_001373705.1:p.Arg80His missense NM_001386777.1:c.239G>A NP_001373706.1:p.Arg80His missense NM_001386788.1:c.239G>A NP_001373717.1:p.Arg80His missense NM_001390.5:c.239G>A NP_001381.2:p.Arg80His missense NM_001391.5:c.239G>A NP_001382.2:p.Arg80His missense NM_001392.5:c.239G>A NP_001383.2:p.Arg80His missense NM_032975.4:c.239G>A NP_116757.2:p.Arg80His missense NM_032978.7:c.239G>A NP_116760.2:p.Arg80His missense NM_032979.5:c.239G>A NP_116761.2:p.Arg80His missense NC_000018.10:g.34794127G>A NC_000018.9:g.32374091G>A NG_009201.1:g.305838G>A LRG_756:g.305838G>A LRG_756t1:c.239G>A LRG_756p1:p.Arg80His LRG_756t2:c.239G>A LRG_756p2:p.Arg80His LRG_756t3:c.239G>A LRG_756p3:p.Arg80His LRG_756t4:c.239G>A LRG_756p4:p.Arg80His - Protein change
- R80H
- Other names
- -
- Canonical SPDI
- NC_000018.10:34794126: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
- 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. |
|||
| DTNA | - | - |
GRCh38 GRCh37 |
615 | 657 | |
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 (1) |
criteria provided, single submitter
|
Mar 7, 2021 | RCV000458154.8 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Feb 5, 2018 | RCV000786307.2 |
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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|---|---|---|---|---|---|
|
Uncertain significance
(Mar 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Left ventricular noncompaction 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000553262.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant has not been reported in the literature in individuals with DTNA-related disease. ClinVar contains an entry for this variant (Variation ID: 411865). This variant is present in population databases (rs774912781, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces arginine with histidine at codon 80 of the DTNA protein (p.Arg80His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. (less)
|
|
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Uncertain significance
(Feb 05, 2018)
|
no assertion criteria provided
Method: provider interpretation
|
not provided
Affected status: unknown
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925075.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
p.Arg80His (c.239G>A) in exon 4 of the DTNA gene (NM_032978.6) Chromosome location 18:32374091 G / A Based on the information reviewed below, we classify this … (more)
p.Arg80His (c.239G>A) in exon 4 of the DTNA gene (NM_032978.6) Chromosome location 18:32374091 G / A Based on the information reviewed below, we classify this as a variant of uncertain significance (VUS)concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. According to the Invitae report, this variant has not been reported in the literature in association with disease. This is a conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a positively-charged Histidine. Arginine at this location is highly conserved across ~100 vertebrate species for which we have data. However, Histidine is the default amino acid in at least one species. There are no Likely Pathogenic or Pathogenic variants currently listed in ClinVar within 10 amino acids to either side. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant was reported in 17 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 "Other ancestry", 2 East-Asian, 10 non-Finnish European, 2 Latino (out of 17,196, MAF = 0.006%), and 1 African ancestry individual. Ovarall minor allele frequency (MAF) = 0.006%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases (less)
|
Comment:
Comment:
p.Arg80His (c.239G>A) in exon 4 of the DTNA gene (NM_032978.6) Chromosome location 18:32374091 G / A Based on the information reviewed below, we classify this as a variant of uncertain significance (VUS)concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. According to the Invitae report, this variant has not been reported in the literature in association with disease. This is a conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a positively-charged Histidine. Arginine at this location is highly conserved across ~100 vertebrate species for which we have data. However, Histidine is the default amino acid in at least one species. There are no Likely Pathogenic or Pathogenic variants currently listed in ClinVar within 10 amino acids to either side. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant was reported in 17 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 "Other ancestry", 2 East-Asian, 10 non-Finnish European, 2 Latino (out of 17,196, MAF = 0.006%), and 1 African ancestry individual. Ovarall minor allele frequency (MAF) = 0.006%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases
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:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant has not been reported in the literature in individuals with DTNA-related disease. ClinVar contains an entry for this variant (Variation ID: 411865). This variant is present in population databases (rs774912781, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces arginine with histidine at codon 80 of the DTNA protein (p.Arg80His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.
Comment:
p.Arg80His (c.239G>A) in exon 4 of the DTNA gene (NM_032978.6) Chromosome location 18:32374091 G / A Based on the information reviewed below, we classify this as a variant of uncertain significance (VUS)concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. According to the Invitae report, this variant has not been reported in the literature in association with disease. This is a conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a positively-charged Histidine. Arginine at this location is highly conserved across ~100 vertebrate species for which we have data. However, Histidine is the default amino acid in at least one species. There are no Likely Pathogenic or Pathogenic variants currently listed in ClinVar within 10 amino acids to either side. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant was reported in 17 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 "Other ancestry", 2 East-Asian, 10 non-Finnish European, 2 Latino (out of 17,196, MAF = 0.006%), and 1 African ancestry individual. Ovarall minor allele frequency (MAF) = 0.006%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. | Kobayashi Y | Genome medicine | 2017 | PMID: 28166811 |
Text-mined citations for rs774912781 ...
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 Sep 29, 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.