rs144261171
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP6
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
NM_001927.4 missense
Scores
12
5
3
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: {Likely_benign=1, Uncertain_significance=12, Benign=1}. Variant chr2-219420151-G-A is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DES | NM_001927.4 | c.635G>A | p.Arg212Gln | missense_variant | 2/9 | ENST00000373960.4 | NP_001918.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DES | ENST00000373960.4 | c.635G>A | p.Arg212Gln | missense_variant | 2/9 | 1 | NM_001927.4 | ENSP00000363071.3 | ||
| 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 0.000204 AC: 31AN: 152214Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000239 AC: 60AN: 251478Hom.: 0 AF XY: 0.000302 AC XY: 41AN XY: 135908
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GnomAD4 exome AF: 0.000244 AC: 357AN: 1461888Hom.: 1 Cov.: 36 AF XY: 0.000256 AC XY: 186AN XY: 727244
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GnomAD4 genome 0.000204 AC: 31AN: 152332Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74486
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:14Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 12, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 06, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2024 | 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) - |
| 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 | 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 | Genetic Services Laboratory, University of Chicago | Dec 20, 2016 | - - |
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at