rs57639980

chr2-219421350-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001927.4(DES):c.1034T>C(p.Leu345Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L345L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.80

Genes affected

DES (HGNC:2770): (desmin) This gene encodes a muscle-specific class III intermediate filament. Homopolymers of this protein form a stable intracytoplasmic filamentous network connecting myofibrils to each other and to the plasma membrane. Mutations in this gene are associated with desmin-related myopathy, a familial cardiac and skeletal myopathy (CSM), and with distal myopathies. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 2-219421350-T-C is Pathogenic according to our data. Variant chr2-219421350-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219421350-T-C is described in Lovd as [Pathogenic]. Variant chr2-219421350-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.1034T>C	p.Leu345Pro	missense_variant	6/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.1034T>C	p.Leu345Pro	missense_variant	6/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.508T>C		non_coding_transcript_exon_variant	5/8	4
DES	ENST00000492726.1	n.429T>C		non_coding_transcript_exon_variant	5/6	4
DES	ENST00000683013.1	n.422T>C		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 03, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant caused disruption of mitochondrial structures (PMID: 16217025). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	DES: PP1:Strong, PM1, PM2, PS3:Moderate, PS4:Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 03, 2020	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Desmin-related myofibrillar myopathy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2022	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 345 of the DES protein (p.Leu345Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant myofibrillar myopathy (PMID: 10545598). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16825). 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. Experimental studies have shown that this missense change affects DES function (PMID: 10545598, 18563598). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.98		Loss of stability (P = 0.0113);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs57639980; hg19: chr2-220286072;