NM_004006.3(DMD):c.4996C>T (p.Arg1666Ter) AND Duchenne muscular dystrophy

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000545335.16

Allele description [Variation Report for NM_004006.3(DMD):c.4996C>T (p.Arg1666Ter)]

NM_004006.3(DMD):c.4996C>T (p.Arg1666Ter)

Gene:

DMD:dystrophin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp21.1

Genomic location:

Preferred name:

NM_004006.3(DMD):c.4996C>T (p.Arg1666Ter)

Other names:

NP_003997.1:p.Arg1666*

HGVS:

NC_000023.11:g.32365049G>A
NG_012232.1:g.979561C>T
NM_000109.4:c.4972C>T
NM_004006.3:c.4996C>TMANE SELECT
NM_004009.3:c.4984C>T
NM_004010.3:c.4627C>T
NM_004011.4:c.973C>T
NM_004012.4:c.964C>T
NP_000100.3:p.Arg1658Ter
NP_003997.1:p.Arg1666Ter
NP_003997.2:p.Arg1666Ter
NP_004000.1:p.Arg1662Ter
NP_004001.1:p.Arg1543Ter
NP_004002.3:p.Arg325Ter
NP_004003.2:p.Arg322Ter
LRG_199t1:c.4996C>T
LRG_199:g.979561C>T
LRG_199p1:p.Arg1666Ter
NC_000023.10:g.32383166G>A
NM_004006.2:c.4996C>T
NM_004006.3:c.4996C>T

Protein change:

R1543*

Links:

dbSNP: rs398123973

NCBI 1000 Genomes Browser:

rs398123973

Molecular consequence:

NM_000109.4:c.4972C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004006.3:c.4996C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004009.3:c.4984C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004010.3:c.4627C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004011.4:c.973C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004012.4:c.964C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Duchenne muscular dystrophy (DMD)
Synonyms:: Muscular dystrophy, pseudohypertrophic progressive, Duchenne type
Identifiers:: MONDO: MONDO:0010679; MedGen: C0013264; Orphanet: 98896; OMIM: 310200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000625911	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 19, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16770791, 25007885, 11524473, 15351422, 17253928, 19760747, 19959795, 21396098, 28492532
SCV001141671	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001251804	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 3, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004047492	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Van Deutekom JC, Fokkema IF, Van Ommen GJ, Den Dunnen JT.

Muscle Nerve. 2006 Aug;34(2):135-44. Review.

PubMed [citation]

PMID:: 16770791

New variants, challenges and pitfalls in DMD genotyping: implications in diagnosis, prognosis and therapy.

Santos R, Gonçalves A, Oliveira J, Vieira E, Vieira JP, Evangelista T, Moreno T, Santos M, Fineza I, Bronze-da-Rocha E.

J Hum Genet. 2014 Aug;59(8):454-64. doi: 10.1038/jhg.2014.54. Epub 2014 Jul 10.

PubMed [citation]

PMID:: 25007885

See all PubMed Citations (10)

Details of each submission

From Invitae, SCV000625911.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001141671.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV001251804.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047492.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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