NM_001927.4(DES):c.2T>C (p.Met1Thr) AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Jun 29, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001377481.1

Allele description [Variation Report for NM_001927.4(DES):c.2T>C (p.Met1Thr)]

NM_001927.4(DES):c.2T>C (p.Met1Thr)

Gene:
DES:desmin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q35
Genomic location:
Preferred name:
NM_001927.4(DES):c.2T>C (p.Met1Thr)
HGVS:
  • NC_000002.12:g.219418464T>C
  • NG_008043.1:g.5088T>C
  • NG_046330.1:g.18856T>C
  • NM_001382708.1:c.2T>C
  • NM_001382709.1:c.2T>C
  • NM_001382710.1:c.2T>C
  • NM_001382711.1:c.2T>C
  • NM_001382712.1:c.2T>C
  • NM_001382713.1:c.2T>C
  • NM_001927.4:c.2T>CMANE SELECT
  • NP_001369637.1:p.Met1Thr
  • NP_001369638.1:p.Met1Thr
  • NP_001369639.1:p.Met1Thr
  • NP_001369640.1:p.Met1Thr
  • NP_001369641.1:p.Met1Thr
  • NP_001369642.1:p.Met1Thr
  • NP_001918.3:p.Met1Thr
  • LRG_380:g.5088T>C
  • NC_000002.11:g.220283186T>C
Protein change:
M1T
Molecular consequence:
  • NM_001382708.1:c.2T>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001382709.1:c.2T>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001382710.1:c.2T>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001382711.1:c.2T>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001382712.1:c.2T>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001382713.1:c.2T>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001927.4:c.2T>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001382708.1:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001382709.1:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001382710.1:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001382711.1:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001382712.1:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001382713.1:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001927.4:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]

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
Name:
Muscular dystrophy, limb-girdle, type 2R (LGMD2R)
Synonyms:
Autosomal recessive limb-girdle muscular dystrophy type 2R
Identifiers:
MONDO: MONDO:0014129; MedGen: C3809137; Orphanet: 363543

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001574822Invitaecriteria provided, single submitter
Likely pathogenic
(Jun 29, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A series of Chinese patients with desminopathy associated with six novel and one reported mutations in the desmin gene.

Hong D, Wang Z, Zhang W, Xi J, Lu J, Luan X, Yuan Y.

Neuropathol Appl Neurobiol. 2011 Apr;37(3):257-70. doi: 10.1111/j.1365-2990.2010.01112.x.

PubMed [citation]
PMID:
20696008

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV001574822.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change affects the initiator methionine of the DES mRNA. The next in-frame methionine is located at codon 263. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DES-related conditions. This variant disrupts the initiator methionine in DES. If translation initiates from the next-in-frame methionine, the DES protein would no longer include the region containing p.Ser12 amino acid residue. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20696008, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Oct 7, 2021

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