NM_001927.4(DES):c.1366G>A (p.Gly456Arg) AND Desmin-related myofibrillar myopathy

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 22, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001852772.6

Allele description [Variation Report for NM_001927.4(DES):c.1366G>A (p.Gly456Arg)]

NM_001927.4(DES):c.1366G>A (p.Gly456Arg)

Gene:

DES:desmin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_001927.4(DES):c.1366G>A (p.Gly456Arg)

HGVS:

NC_000002.12:g.219425740G>A
NG_008043.1:g.12364G>A
NM_001927.4:c.1366G>AMANE SELECT
NP_001918.3:p.Gly456Arg
LRG_380t1:c.1366G>A
LRG_380:g.12364G>A
NC_000002.11:g.220290462G>A
NM_001927.3:c.1366G>A
c.1366G>A

Protein change:

G456R

Links:

dbSNP: rs397516690

NCBI 1000 Genomes Browser:

rs397516690

Molecular consequence:

NM_001927.4:c.1366G>A - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002196116	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 5, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32150461, 28492532
SCV004708214	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 22, 2024)	germline	research	PubMed (3) [See all records that cite these PMIDs] 37712079, 35958417, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002196116

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 5, 2023)

germline

clinical testing

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

SCV004708214

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 22, 2024)

germline

research

PubMed (3)
[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	yes	1	1	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic Testing for Diagnosis of Hypertrophic Cardiomyopathy Mimics: Yield and Clinical Significance.

Hoss S, Habib M, Silver J, Care M, Chan RH, Hanneman K, Morel CF, Iwanochko RM, Gollob MH, Rakowski H, Adler A.

Circ Genom Precis Med. 2020 Apr;13(2):e002748. doi: 10.1161/CIRCGEN.119.002748. Epub 2020 Mar 9.

PubMed [citation]

PMID:: 32150461

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002196116.3

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

Description

This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32150461). ClinVar contains an entry for this variant (Variation ID: 44251). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DES protein function. 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 456 of the DES protein (p.Gly456Arg).

#	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 Neurogenomics Lab, Neuroscience Institute, University Of Cape Town, SCV004708214.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (3)

Description

PM2_Supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed). PM1 not met: pathogenic DES variants are distributed throughout the protein. PP3_Moderate: REVEL score is 0.884. PM3 Met: max 1 point awarded for 2 homozygous observations of variant in probands with consistent phenotype for disorder. PS4_Supporting: Variant found in 1 proband (homozygous) with consistent phenotype for disorder. This proband counted under PS4 as max points reached for homozygous observations counted under PM3. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases

#	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		1	not provided	1	not provided

Last Updated: Sep 29, 2024

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