NM_001927.4(DES):c.1216C>T (p.Arg406Trp) AND Myofibrillar myopathy 1

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 20, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000018320.36

Allele description [Variation Report for NM_001927.4(DES):c.1216C>T (p.Arg406Trp)]

NM_001927.4(DES):c.1216C>T (p.Arg406Trp)

Gene:
DES:desmin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q35
Genomic location:
Preferred name:
NM_001927.4(DES):c.1216C>T (p.Arg406Trp)
Other names:
p.R406W:CGG>TGG
HGVS:
  • NC_000002.12:g.219421532C>T
  • NG_008043.1:g.8156C>T
  • NM_001927.4:c.1216C>TMANE SELECT
  • NP_001918.3:p.Arg406Trp
  • LRG_380t1:c.1216C>T
  • LRG_380:g.8156C>T
  • NC_000002.11:g.220286254C>T
  • NM_001927.3:c.1216C>T
  • P17661:p.Arg406Trp
Protein change:
R406W; ARG406TRP
Links:
UniProtKB: P17661#VAR_042458; OMIM: 125660.0007; dbSNP: rs121913003
NCBI 1000 Genomes Browser:
rs121913003
Molecular consequence:
  • NM_001927.4:c.1216C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Myofibrillar myopathy 1 (MFM1)
Synonyms:
MYOPATHY, MYOFIBRILLAR, DESMIN-RELATED; Desminopathy; Desmin related myopathy (former name); See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011076; MedGen: C1832370; Orphanet: 98909; OMIM: 601419

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000038599OMIMno assertion criteria providedPathogenic
(Jun 1, 2000)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000265769Center for Genetic Medicine Research,Children's National Medical Centercriteria provided, single submitter
Likely pathogenic
(Dec 1, 2015)
unknownresearch

PubMed (1)
[See all records that cite this PMID]

SCV000271350Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Mar 11, 2015)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001149752Institute of Human Genetics, Klinikum rechts der Isarcriteria provided, single submitter
Pathogenic
(Aug 20, 2018)
de novoclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyes1not providednot provided1not providedclinical testing
not providedgermlinenot provided11not providednot providednot providedliterature only, clinical testing
not providedunknownyesnot providednot providednot providednot providednot providedresearch

Citations

PubMed

Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases.

Punetha J, Kesari A, Uapinyoying P, Giri M, Clarke NF, Waddell LB, North KN, Ghaoui R, O'Grady GL, Oates EC, Sandaradura SA, Bönnemann CG, Donkervoort S, Plotz PH, Smith EC, Tesi-Rocha C, Bertorini TE, Tarnopolsky MA, Reitter B, Hausmanowa-Petrusewicz I, Hoffman EP.

J Neuromuscul Dis. 2016 May 27;3(2):209-225.

PubMed [citation]
PMID:
27854218

A series of West European patients with severe cardiac and skeletal myopathy associated with a de novo R406W mutation in desmin.

Dagvadorj A, Olivé M, Urtizberea JA, Halle M, Shatunov A, Bönnemann C, Park KY, Goebel HH, Ferrer I, Vicart P, Dalakas MC, Goldfarb LG.

J Neurol. 2004 Feb;251(2):143-9.

PubMed [citation]
PMID:
14991347
See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000038599.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a sporadic case of cardiac and skeletal myopathy (MFM1; 601419), Park et al. (2000) demonstrated heterozygosity for an arg406-to-trp (R406W) mutation in the DES gene. The mutation was not found in the patient's father, mother, or sister. Alternative paternity was excluded. Haplotype analysis indicated that the patient's father was a germline mosaic for the desmin mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Center for Genetic Medicine Research,Children's National Medical Center, SCV000265769.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000271350.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (7)

Description

The p.Arg406Trp variant in DES is absent from large populations sequenced by the Exome Aggregation Consortium (exac.broadinstitute.org/) but has been reported i n at least 5 individuals with clinical features of desminopathies, including con duction system disease +/-cardiomyopathy (DCM and RCM) and skeletal myopathy (sa me individuals reported in multiple papers; Dalakas 2000, Park 2000, Dagvadirj 2 004, Olive 2004, Wahbi 2012). In at least least 4 individuals the variant had oc curred de novo (paternity confirmed; same individuals reported in multiple paper s; Dalakas 2000, Park 2000, Dagvadirj 2004, Olive 2004). In vitro functional stu dies provide some evidence that the p.Arg406Trp variant impacts protein function (Park 2000, Chourbagi 2011). However, these types of assays sometimes do not ac curately represent biological function. In summary, this variant meets our crite ria to be classified as pathogenic for desminopathy with cardiac and skeletal my opathy involvement in an autosomal dominant manner (http://www.partners.org/pers onalizedmedicine/LMM) based upon absence from the general population and de novo occurrence.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Institute of Human Genetics, Klinikum rechts der Isar, SCV001149752.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyes1bloodnot provided1not providednot providednot provided

Last Updated: Oct 20, 2021

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