NM_001927.4(DES):c.1396C>T (p.Gln466Ter) AND Desmin-related myofibrillar myopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 26, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004018194.1

Allele description [Variation Report for NM_001927.4(DES):c.1396C>T (p.Gln466Ter)]

NM_001927.4(DES):c.1396C>T (p.Gln466Ter)

Gene:

DES:desmin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_001927.4(DES):c.1396C>T (p.Gln466Ter)

HGVS:

NC_000002.12:g.219425973C>T
NG_008043.1:g.12597C>T
NM_001382708.1:c.1393C>T
NM_001382709.1:c.964C>T
NM_001382710.1:c.1327C>T
NM_001382711.1:c.1375C>T
NM_001382712.1:c.1371+228C>T
NM_001382713.1:c.1126C>T
NM_001927.4:c.1396C>TMANE SELECT
NP_001369637.1:p.Gln465Ter
NP_001369638.1:p.Gln322Ter
NP_001369639.1:p.Gln443Ter
NP_001369640.1:p.Gln459Ter
NP_001369642.1:p.Gln376Ter
NP_001918.3:p.Gln466Ter
NP_001918.3:p.Gln466Ter
LRG_380t1:c.1396C>T
LRG_380:g.12597C>T
LRG_380p1:p.Gln466Ter
NC_000002.11:g.220290695C>T
NM_001927.3:c.1396C>T

Protein change:

Q322*

Molecular consequence:

NM_001382712.1:c.1371+228C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001382708.1:c.1393C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001382709.1:c.964C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001382710.1:c.1327C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001382711.1:c.1375C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001382713.1:c.1126C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001927.4:c.1396C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Desmin-related myofibrillar myopathy (MFM1)
Synonyms:: Desminopathy; Desmin related myopathy (former name); Desmin storage myopathy (former name); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011076; MedGen: C1832370; Orphanet: 363543; Orphanet: 98909; OMIM: 601419

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004848731	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Aug 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848731

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Aug 26, 2022)

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848731.1

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

Description

The p.Gln466X variant in DES has not been previously reported in individuals with desmin-related myopathy and was absent in large population databases. This nonsense variant leads to a premature termination codon at position 466, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DES gene is an established disease mechanism in desmin-related myopathy. In summary, although additional studies are required to fully establish its clinical significance, the p.Gln466X variant is likely pathogenic for autosomal dominant desmin-related myopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.

#	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

Last Updated: May 1, 2024

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