NM_001927.4(DES):c.380G>C (p.Arg127Pro) AND Desmin-related myofibrillar myopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 23, 2023
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:: RCV000547988.9

Allele description [Variation Report for NM_001927.4(DES):c.380G>C (p.Arg127Pro)]

NM_001927.4(DES):c.380G>C (p.Arg127Pro)

Gene:

DES:desmin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_001927.4(DES):c.380G>C (p.Arg127Pro)

Other names:

p.R127P:CGC>CCC

HGVS:

NC_000002.12:g.219418842G>C
NG_008043.1:g.5466G>C
NM_001927.4:c.380G>CMANE SELECT
NP_001918.3:p.Arg127Pro
LRG_380t1:c.380G>C
LRG_380:g.5466G>C
NC_000002.11:g.220283564G>C
NM_001927.3:c.380G>C
c.380G>C

Protein change:

R127P

Links:

dbSNP: rs397516694

NCBI 1000 Genomes Browser:

rs397516694

Molecular consequence:

NM_001927.4:c.380G>C - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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Homo sapiens activating transcription factor 2 (ATF2), transcript variant 9, non...
Homo sapiens activating transcription factor 2 (ATF2), transcript variant 9, non-coding RNA
gi|1701969363|ref|NR_045770.2|

Nucleotide
Homo sapiens G protein-coupled receptor 155, mRNA (cDNA clone IMAGE:5263578), co...
Homo sapiens G protein-coupled receptor 155, mRNA (cDNA clone IMAGE:5263578), complete cds
gi|23331079|gb|BC036681.1|

Nucleotide
SRX20602156 (1)
SRA

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000654173	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25179549, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000654173

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 23, 2023)

germline

clinical testing

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

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

Targeted analysis of whole genome sequence data to diagnose genetic cardiomyopathy.

Golbus JR, Puckelwartz MJ, Dellefave-Castillo L, Fahrenbach JP, Nelakuditi V, Pesce LL, Pytel P, McNally EM.

Circ Cardiovasc Genet. 2014 Dec;7(6):751-759. doi: 10.1161/CIRCGENETICS.113.000578. Epub 2014 Sep 1.

PubMed [citation]

PMID:: 25179549
PMCID:: PMC4270910

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000654173.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 127 of the DES protein (p.Arg127Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 25179549). ClinVar contains an entry for this variant (Variation ID: 44259). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DES protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DES function (PMID: 25179549). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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