rs144261171

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2PP3BS1_Supporting

The NM_001927.4(DES):c.635G>A(p.Arg212Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,614,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

DES
NM_001927.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:2

Conservation

PhyloP100: 9.86

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1I
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
myofibrillar myopathy 1
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
atrioventricular block
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neurogenic scapuloperoneal syndrome, Kaeser type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DES links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.7729 (below the threshold of 3.09). Trascript score misZ: 0.36303 (below the threshold of 3.09). GenCC associations: The gene is linked to myofibrillar myopathy 1, dilated cardiomyopathy 1I, atrioventricular block, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, familial isolated dilated cardiomyopathy, neurogenic scapuloperoneal syndrome, Kaeser type.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000204 (31/152332) while in subpopulation AMR AF = 0.000653 (10/15306). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4 link	c.635G>A	p.Arg212Gln	missense_variant	Exon 2 of 9	ENST00000373960.4	NP_001918.3	P17661Q53SB5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DES	ENST00000373960.4 link	c.635G>A	p.Arg212Gln	missense_variant	Exon 2 of 9	1	NM_001927.4	ENSP00000363071.3	P17661
DES	ENST00000477226.6 link	n.109G>A		non_coding_transcript_exon_variant	Exon 1 of 8	4
DES	ENST00000492726.1 link	n.30G>A		non_coding_transcript_exon_variant	Exon 1 of 6	4
DES	ENST00000683013.1 link	n.-73G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000239

AC:

AN:

251478

AF XY:

0.000302

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000244

AC:

357

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

186

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000313

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000282

AC:

314

AN:

1112008

Other (OTH)

AF:

0.000315

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000204

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41574

American (AMR)

AF:

0.000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000253

Hom.:

Bravo

AF:

0.000249

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Oct 06, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 12, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in individuals with left ventricular noncompaction cardiomyopathy (LVNC), dilated cardiomyopathy (DCM), and sudden unexplained death however, multiple individuals harbored additional cardiogenetic variants (PMID: 27930701, 28798025, 32880476, Ridha A et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29926427, 28798025, 32142595, 32880476, 30190612, 35130036, 27930701, RidhaA2015[CaseReport], 30564623, 26807690) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:3

Aug 06, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg212Gln variant in DES has not been previously reported in individuals w ith cardiomyopathy but has been identified in 18/66736 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1 44261171). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg212Gln variant is uncertain. -

Aug 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DES c.635G>A (p.Arg212Gln) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 251478 control chromosomes. The observed variant frequency is approximately 7.63 fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is benign. c.635G>A has been reported in the literature in a cognitive and developmental cohort (Pizzo_2019), in an individual with sudden unexpected death (Sanchez_2016), Dilated Cardiomyopathy (Verdonschot_2020) and left ventricular non-compaction (2017). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28798025, 30190612, 27930701, 32880476). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=9) and benign/likely benign (n=2) citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Dec 20, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Desmin-related myofibrillar myopathy

Uncertain:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 212 of the DES protein (p.Arg212Gln). This variant is present in population databases (rs144261171, gnomAD 0.03%). This missense change has been observed in individual(s) with DES-related conditions (PMID: 27930701, 32880476). ClinVar contains an entry for this variant (Variation ID: 178015). Invitae Evidence 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 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. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiovascular phenotype

Uncertain:2

Nov 06, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R212Q variant (also known as c.635G>A), located in coding exon 2 of the DES gene, results from a G to A substitution at nucleotide position 635. The arginine at codon 212 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in individuals from sudden death, left ventricular non-compaction cardiomyopathy, dilated cardiomyopathy genetic testing, and neurodevelopmental cohorts; however, in several cases, clinical detail was limited and the variant co-occurred with variants in other genes (Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Pizzo L et al. Genet. Med., 2019 04;21:816-825). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, BS1 -

Dilated cardiomyopathy 1I

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Apr 12, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Cardiomyopathy

Uncertain:1

Dec 03, 2019

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Uncertain:1

Oct 16, 2020

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

We observed a c.635G>A (p.R212Q) genetic variant in a male 2-month old proband, diagnosed with multiple heart abnormalities (dialted cardiomyopathy, multiple ventricular septal defects, left ventricular noncompaction, patent ductus arteriosus). To our knowledge, the frequency of the p.R212Q genetic variant is 0.00015-0.00040, which is compatible to the frequency of HCM and DCM. Online bioinformatic resources predict the p.R212Q genetic vatiant to be probably pathogenic. However, in the absence of the family screening data and/or functional studies, we could only classify the p.R212Q genetic variant as a variant with uncertain clinical significance. -

Left ventricular noncompaction cardiomyopathy

Uncertain:1

Mar 21, 2014

Blueprint Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Myofibrillar Myopathy, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neurogenic scapuloperoneal syndrome, Kaeser type

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

CardioboostCm

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.84

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.1

PhyloP100

9.9

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.85

Sift

Benign

0.061

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.91

MVP

0.98

MPC

0.020

ClinPred

0.48

GERP RS

4.6

Varity_R

0.68

gMVP

0.87

Mutation Taster

=32/68

disease causing

(source)

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

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rs144261171

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over