Variant summary: DMD c.4996C>T (p.Arg1666X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183156 control chromosomes (gnomAD). c.4996C>T has been reported in the literature in individuals affected with Dystrophinopathies (example: Tuffery-Giraud_2004, Spitali_2009, and Magri_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_004006.3(DMD):c.4996C>T (p.Arg1666Ter)
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
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_004006.3(DMD):c.4996C>T (p.Arg1666Ter)
Variation ID: 94646 Accession: VCV000094646.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp21.1 X: 32365049 (GRCh38) [ NCBI UCSC ] X: 32383166 (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 19, 2017 Feb 20, 2024 Sep 19, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004006.3:c.4996C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003997.2:p.Arg1666Ter nonsense NM_000109.4:c.4972C>T NP_000100.3:p.Arg1658Ter nonsense NM_004009.3:c.4984C>T NP_004000.1:p.Arg1662Ter nonsense NM_004010.3:c.4627C>T NP_004001.1:p.Arg1543Ter nonsense NM_004011.4:c.973C>T NP_004002.3:p.Arg325Ter nonsense NM_004012.4:c.964C>T NP_004003.2:p.Arg322Ter nonsense NC_000023.11:g.32365049G>A NC_000023.10:g.32383166G>A NG_012232.1:g.979561C>T LRG_199:g.979561C>T LRG_199t1:c.4996C>T LRG_199p1:p.Arg1666Ter - Protein change
- R1666*, R1658*, R1662*, R325*, R1543*, R322*
- Other names
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NP_003997.1:p.Arg1666*
- Canonical SPDI
- NC_000023.11:32365048: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.
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- 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. |
|||
| DMD | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9338 | 9631 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 31, 2022 | RCV000516386.14 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 19, 2023 | RCV000545335.17 | |
|
Dystrophin deficiency
|
Pathogenic (1) |
no assertion criteria provided
|
May 24, 2021 | RCV001831854.3 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 21, 2023 | RCV003323389.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Aug 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000613123.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
|
|
Pathogenic
(Feb 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000700486.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Pathogenic
(Jul 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Qualitative or quantitative defects of dystrophin
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004029848.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: DMD c.4996C>T (p.Arg1666X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: DMD c.4996C>T (p.Arg1666X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183156 control chromosomes (gnomAD). c.4996C>T has been reported in the literature in individuals affected with Dystrophinopathies (example: Tuffery-Giraud_2004, Spitali_2009, and Magri_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Duchenne muscular dystrophy
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047492.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The frame shift variant c.4996C>T(p.Arg1666Ter) has been reported previously in patients affected with Duchenne muscular dystrophy (Magri F et al., 2011; Stockley TL et al., … (more)
The frame shift variant c.4996C>T(p.Arg1666Ter) has been reported previously in patients affected with Duchenne muscular dystrophy (Magri F et al., 2011; Stockley TL et al., 2006). This sequence change creates a premature translational stop signal (p.Arg1666) in the DMD gene. It is expected to result in an absent or disrupted protein product. The nucleotide change in DMD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The c.4996C>T(p.Arg1666Ter) variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Muscular dystrophy (present)
|
|
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Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021139.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Sep 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Duchenne muscular dystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000625911.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1666*) in the DMD gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg1666*) in the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (PMID: 11524473, 15351422, 17253928, 19760747, 19959795, 21396098). ClinVar contains an entry for this variant (Variation ID: 94646). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Duchenne muscular dystrophy
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001141671.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
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Pathogenic
(May 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Duchenne muscular dystrophy
Affected status: yes
Allele origin:
unknown
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251804.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
|
|
|
Pathogenic
(May 24, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Becker muscular dystrophy
Cardiomyopathy Duchenne muscular dystrophy Dystrophin deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002093552.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
Comment:
Comment:
The frame shift variant c.4996C>T(p.Arg1666Ter) has been reported previously in patients affected with Duchenne muscular dystrophy (Magri F et al., 2011; Stockley TL et al., 2006). This sequence change creates a premature translational stop signal (p.Arg1666) in the DMD gene. It is expected to result in an absent or disrupted protein product. The nucleotide change in DMD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The c.4996C>T(p.Arg1666Ter) variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg1666*) in the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (PMID: 11524473, 15351422, 17253928, 19760747, 19959795, 21396098). ClinVar contains an entry for this variant (Variation ID: 94646). For these reasons, this variant has been classified as Pathogenic.
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:
Variant summary: DMD c.4996C>T (p.Arg1666X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183156 control chromosomes (gnomAD). c.4996C>T has been reported in the literature in individuals affected with Dystrophinopathies (example: Tuffery-Giraud_2004, Spitali_2009, and Magri_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The frame shift variant c.4996C>T(p.Arg1666Ter) has been reported previously in patients affected with Duchenne muscular dystrophy (Magri F et al., 2011; Stockley TL et al., 2006). This sequence change creates a premature translational stop signal (p.Arg1666) in the DMD gene. It is expected to result in an absent or disrupted protein product. The nucleotide change in DMD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The c.4996C>T(p.Arg1666Ter) variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg1666*) in the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (PMID: 11524473, 15351422, 17253928, 19760747, 19959795, 21396098). ClinVar contains an entry for this variant (Variation ID: 94646). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Repository of mutations from Oman: The entry point to a national mutation database. | Rajab A | F1000Research | 2015 | PMID: 26594346 |
| New variants, challenges and pitfalls in DMD genotyping: implications in diagnosis, prognosis and therapy. | Santos R | Journal of human genetics | 2014 | PMID: 25007885 |
| Clinical and molecular characterization of a cohort of patients with novel nucleotide alterations of the Dystrophin gene detected by direct sequencing. | Magri F | BMC medical genetics | 2011 | PMID: 21396098 |
| One hundred twenty-one dystrophin point mutations detected from stored DNA samples by combinatorial denaturing high-performance liquid chromatography. | Torella A | The Journal of molecular diagnostics : JMD | 2010 | PMID: 19959795 |
| Exon skipping-mediated dystrophin reading frame restoration for small mutations. | Spitali P | Human mutation | 2009 | PMID: 19760747 |
| Regional genomic instability predisposes to complex dystrophin gene rearrangements. | Oshima J | Human genetics | 2009 | PMID: 19449031 |
| Simultaneous MLPA-based multiplex point mutation and deletion analysis of the dystrophin gene. | Bunyan DJ | Molecular biotechnology | 2007 | PMID: 17435279 |
| Strategy for comprehensive molecular testing for Duchenne and Becker muscular dystrophies. | Stockley TL | Genetic testing | 2006 | PMID: 17253928 |
| Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. | Aartsma-Rus A | Muscle & nerve | 2006 | PMID: 16770791 |
| Mutation rates in the dystrophin gene: a hotspot of mutation at a CpG dinucleotide. | Buzin CH | Human mutation | 2005 | PMID: 15643612 |
| The role of muscle biopsy in analysis of the dystrophin gene in Duchenne muscular dystrophy: experience of a national referral centre. | Tuffery-Giraud S | Neuromuscular disorders : NMD | 2004 | PMID: 15351422 |
| Diagnosis of Duchenne dystrophy by enhanced detection of small mutations. | Mendell JR | Neurology | 2001 | PMID: 11524473 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DMD | - | - | - | - |
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Text-mined citations for rs398123973 ...
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.