NM_001927.4(DES):c.347A>G (p.Asn116Ser) AND Desmin-related myofibrillar myopathy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 29, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001384253.16

Allele description [Variation Report for NM_001927.4(DES):c.347A>G (p.Asn116Ser)]

NM_001927.4(DES):c.347A>G (p.Asn116Ser)

Gene:

DES:desmin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_001927.4(DES):c.347A>G (p.Asn116Ser)

HGVS:

NC_000002.12:g.219418809A>G
NG_008043.1:g.5433A>G
NM_001927.4:c.347A>GMANE SELECT
NP_001918.3:p.Asn116Ser
LRG_380t1:c.347A>G
LRG_380:g.5433A>G
NC_000002.11:g.220283531A>G
NM_001927.3:c.347A>G
P17661:p.Asn116Ser

Protein change:

N116S

Links:

UniProtKB: P17661#VAR_069191; dbSNP: rs267607499

NCBI 1000 Genomes Browser:

rs267607499

Molecular consequence:

NM_001927.4:c.347A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000197520	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Mar 5, 2014)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20829228, 22403400, 24033266
SCV001583679	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22403400, 20829228, 26676851, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000197520

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Mar 5, 2014)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001583679

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (4)
[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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Dual color photoactivation localization microscopy of cardiomyopathy-associated desmin mutants.

Brodehl A, Hedde PN, Dieding M, Fatima A, Walhorn V, Gayda S, Šarić T, Klauke B, Gummert J, Anselmetti D, Heilemann M, Nienhaus GU, Milting H.

J Biol Chem. 2012 May 4;287(19):16047-57. doi: 10.1074/jbc.M111.313841. Epub 2012 Mar 8.

PubMed [citation]

PMID:: 22403400
PMCID:: PMC3346104

See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000197520.4

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

Description

The Asn116Ser variant in DES has been reported in 1 Caucasian individual with ea rly onset ARVC and was confirmed to be a de novo occurrence (Klauke 2010). Data from large population studies is insufficient to assess the frequency of this va riant. Functional studies have shown that the Asn116Ser variant impacts protein function (Klauke 2010, Brodehl 2012). However, these in vitro assays may not acc urately represent biological function. Computational prediction tools and conser vation analysis suggest that this variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, this variant is likely to be pathogenic, though additional studies are required to fu lly establish its clinical significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001583679.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DES function (PMID: 20829228, 22403400). 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. ClinVar contains an entry for this variant (Variation ID: 66411). This missense change has been observed in individual(s) with DES-related conditions (PMID: 20829228, 26676851; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 116 of the DES protein (p.Asn116Ser).

#	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: Nov 3, 2024

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