rs144261171

Positions:

• chr2-219420151-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:2
• Conservation: PhyloP100: 9.86

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• BP6: Variant 2-219420151-G-A is Benign according to our data. Variant chr2-219420151-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178015.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Likely_benign=1, Benign=1}. Variant chr2-219420151-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.635G>A	p.Arg212Gln	missense_variant	2/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.635G>A	p.Arg212Gln	missense_variant	2/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.109G>A		non_coding_transcript_exon_variant	1/8	4
DES	ENST00000492726.1	n.30G>A		non_coding_transcript_exon_variant	1/6	4

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152214 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251478 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135908

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 SAS exome AF: 0.00

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.: 1 Cov.: 36 AF XY: 0.000256 AC XY: 186 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000282

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74486

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2023	Reported in individuals with left ventricular noncompaction cardiomyopathy (LVNC), dilated cardiomyopathy (DCM), and sudden unexplained death (Ridha et al., 2015; Miszalski-Jamka et al., 2017; Sanchez et al., 2016; Verdonschot et al., 2020); however, multiple individuals harbored additional cardiogenetic variants; 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, 27930701, 35130036) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 12, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2014	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2023	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. -

Desmin-related myofibrillar myopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	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). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

Dilated cardiomyopathy 1I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 03, 2019

- -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 16, 2020

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

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Mar 21, 2014

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

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. -

Myofibrillar Myopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neurogenic scapuloperoneal syndrome, Kaeser type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.85
Sift	Benign	0.061	T
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.98
MPC		0.020
ClinPred		0.48	T
GERP RS		4.6
Varity_R		0.68
gMVP		0.87

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: rs144261171; hg19: chr2-220284873; COSMIC: COSV64660055; COSMIC: COSV64660055;