2-219421364-C-T

Position:

chr2-219421364-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_001927.4(DES):c.1048C>T(p.Arg350Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R350P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

DES
NM_001927.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:6O:1

Conservation

PhyloP100: 1.94

Variant links:

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]

DES links:

DES (HGNC:):

DES links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a region_of_interest Interaction with NEB (size 147) in uniprot entity DESM_HUMAN there are 50 pathogenic changes around while only 2 benign (96%) in NM_001927.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-219421365-G-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

PP5

Variant 2-219421364-C-T is Pathogenic according to our data. Variant chr2-219421364-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44244.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Pathogenic=1, not_provided=1, Likely_pathogenic=2}. Variant chr2-219421364-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4 linkuse as main transcript	c.1048C>T	p.Arg350Trp	missense_variant	6/9	ENST00000373960.4	NP_001918.3	P17661Q53SB5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DES	ENST00000373960.4 linkuse as main transcript	c.1048C>T	p.Arg350Trp	missense_variant	6/9	1	NM_001927.4	ENSP00000363071.3	P17661
DES	ENST00000477226.6 linkuse as main transcript	n.522C>T		non_coding_transcript_exon_variant	5/8	4
DES	ENST00000492726.1 linkuse as main transcript	n.443C>T		non_coding_transcript_exon_variant	5/6	4
DES	ENST00000683013.1 linkuse as main transcript	n.436C>T		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251398

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest that desmin protein harboring p.(R350W) results in disruption of desmin filament assembly (Taylor et al., 2007); This variant is associated with the following publications: (PMID: 17439987, 27896284, 29247119, 23299917, 17325244, 20474083, 20448486, 15800015, 22337857, 29926427, 31514951, 28416588, 33500567, 31983221, 32150461, 29386531) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Dilated cardiomyopathy 1I

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with dilated cardiomyopathy 1I (MIM#604765), myofibrillar myopathy 1 (MIM#601419) and Kaeser type neurogenic scapuloperoneal syndrome (MIM#181400) (PMIDs: 29926427, 33373648). (I) 0108 - This gene is associated with both recessive and dominant disease. The majority of disease-associated DES variants exhibit autosomal dominant inheritance, with rare cases of biallelic truncating and missense variants reported for myopathy (PMID: 29926427). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v4: 29 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele count: 65 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated filament domain (DECIPHER). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. Multiple alternative changes, p.(Arg350Pro), p.(Arg350Gln) and p.(Arg350Leu), have been reported. p.(Arg350Pro) has been classified as pathogenic by multiple clinical laboratories, and p.(Arg350Gln) and p.(Arg350Leu) have been classified as VUS by clinical laboratories (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as VUS, likely pathogenic and pathogenic by clinical laboratories in ClinVar. It has also been reported as pathogenic and as VUS in multiple individuals within the literature from cohorts with dilated cardiomyopathy or sudden unexplained death (PMIDs: 17325244, 29247119, 28416588, 29386531, 31983221). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies showed severe disruption of the normal desmin filament assembly with clumping and aggregation of cytoplasmic protein (PMID: 17325244). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 13, 2007	- -

Primary dilated cardiomyopathy

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Sep 29, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Feb 05, 2024	This sequence change in DES is predicted to replace arginine with tryptophan at codon 350, p.(Arg350Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the intermediate filament (IF) rod domain. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.002% (25/1,180,008 alleles) in the European (non-Finnish) population, which is consistent with dilated cardiomyopathy. This variant has been reported in at least seven unrelated individuals with dilated cardiomyopathy (PMID: 17325244, 28416588, 29386531, 31983221, 33823640; ClinVar: SCV000206887.1, SCV001203482.4). An in vitro functional assay with limited validation in neonatal rat myocytes showed that the formation of desmin filaments was affected in the presence of the variant indicating that it impacts protein function (PMID: 17325244). Computational evidence predicts a deleterious effect for the missense substitution (REVEL =0.853). Another missense variant c.1049G>C, p.(Arg350Pro) in the same codon has been classified as pathogenic for DES-related myofibrillar myopathy (ClinVar ID: 16835; PMID: 25394388, 15800015). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2_Supporting, PM5, PP3, PS3_Supporting, PS4_Moderate -

Desmin-related myofibrillar myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 350 of the DES protein (p.Arg350Trp). This variant is present in population databases (rs62636492, gnomAD 0.007%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 17325244, 29247119, 29386531; Invitae). ClinVar contains an entry for this variant (Variation ID: 44244). 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: 17325244). This variant disrupts the p.Arg350 amino acid residue in DES. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15800015, 17439987, 20448486, 25394388, 27393313). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 05, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg350Trp i n DES gene has been reported in 1 55 year old individual with DCM (Taylor 2007). This variant has also been identified in 1/8600 European American chromosomes f rom a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS; dbSNP rs62636492). This could represent a presymptomatic individ ual and the overall low population frequency supports pathogenicity. In vitro st udies showed disruption of the desmin filament assembly, although in vitro assay s do not always accurately reflect biological function (Taylor 2007). Arginine ( Arg) at position 350 is highly conserved evolution and computational analyses (b iochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that t his variant may impact the protein (the accuracy of these tools is unknown). Fin ally, another variant at this position (Arg350Pro) has been reported as a pathog enic variant in individuals with conduction system disease, and cardiac and skel etal myopathy (Bar 2005, Walter 2007, Levin 2010). In summary, the available dat a supports that the Arg350Trp variant may be pathogenic, though additional studi es are needed to fully assess its clinical significance. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 09, 2023

- -

DES-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2024

The DES c.1048C>T variant is predicted to result in the amino acid substitution p.Arg350Trp. This variant was reported in individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy, left ventricular noncompaction, or sudden unexplained deaths (Taylor et al. 2007. PubMed ID: 17325244; Table S3, Lin et al. 2017. PubMed ID: 29247119; Online Table 1, Gigli et al. 2019. PubMed ID: 31514951; Table S1, Hoss et al. 2020. PubMed ID: 32150461; Table S2, Mazzarotto et al. 2021. PubMed ID: 33500567). Functional studies suggested that this variant could disrupt the intracytoplasmic localization (Taylor et al. 2007. PubMed ID: 17325244). However, this variant was also documented in the general population (Andreasen et al. 2013. PubMed ID: 23299917; Table S1, Nouhravesh et al. 2016. PubMed ID: 27896284). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain significance to pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/44244). A different nucleotide substitution affecting the same amino acid (p.Arg350Pro) has been reported to be causative for DES-associated disorders (Bar et al. 2005. PubMed ID: 15800015; Walter et al. 2007. PubMed ID: 17439987). Although we suspect that the c.1048C>T (p.Arg350Trp) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2022

The c.1048C>T (p.R350W) alteration is located in exon 6 (coding exon 6) of the DES gene. This alteration results from a C to T substitution at nucleotide position 1048, causing the arginine (R) at amino acid position 350 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

CardioboostCm

Uncertain

0.15

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.9

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.90

MVP

1.0

MPC

1.5

ClinPred

1.0

GERP RS

2.4

Varity_R

0.92

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over