2-219425727-C-G

Position:

• chr2-219425727-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001927.4(DES):​c.1353C>G​(p.Ile451Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,602,862 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I451I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:3 U:7 O:1
• Conservation: PhyloP100: -2.88

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a region_of_interest Interaction with CRYAB (size 15) in uniprot entity DESM_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4	c.1353C>G	p.Ile451Met	missense_variant	8/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.1353C>G	p.Ile451Met	missense_variant	8/9	1	NM_001927.4	ENSP00000363071	P1
	ENST00000431827.1	n.104+354G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151926 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.0000645 AC: 15 AN: 232466 Hom.: 0 AF XY: 0.0000480 AC XY: 6 AN XY: 125040

Gnomad AFR exome AF: 0.000206

Gnomad AMR exome AF: 0.0000309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000955

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.0000455 AC: 66 AN: 1450936 Hom.: 0 Cov.: 31 AF XY: 0.0000500 AC XY: 36 AN XY: 720562

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.0000466

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000524

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151926 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74198

Gnomad4 AFR AF: 0.0000242

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

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2 Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2023	Reported in association with DCM and HCM, and was shown to segregate with disease in one affected relative from a single family; however, only the DES gene was analyzed in this family (Li et al., 1999; van Lint et al., 2019; Oktay et al., 2023); Identified in three affected relatives from one family with skeletal myopathy; however, only the DES gene was analyzed in these individuals (Dalakas et al., 2003).; Functional studies have been inconsistent in demonstrating a damaging effect (Lapouge et al., 2006; Mavroidis et al., 2008; Sharma et al., 2017; Dalakas et al., 2003; Bar et al., 2007; Chourbagi et al., 2011).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36935760, 16761416, 11052860, 21262226, 17221859, 28470624, 18539904, 16979163, 30403391, 26807690, 30847666, 11728149, 37466024, 12609507, 17105773, 10430757) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2016	- -

Dilated cardiomyopathy 1I Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 03, 1999	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Desmin-related myofibrillar myopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 10, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 451 of the DES protein (p.Ile451Met). This variant is present in population databases (rs121913002, gnomAD 0.02%). This missense change has been observed in individual(s) with DES-related conditions (PMID: 10430757, 10717012, 11728149, 30403391, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16824). 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. Experimental studies have shown that this missense change affects DES function (PMID: 17105773, 17221859, 18539904, 28470624). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 02, 2022

Variant summary: DES c.1353C>G (p.Ile451Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 233386 control chromosomes. The observed variant frequency is approximately 2.1 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.1353C>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy (DCM) (example, Li_1999, Miyamoto_2001, van Lint_2019), in unaffected family members (example, Li_1999, Dalakas_2003), and individuals with skeletal myopathy without DCM (example, Dalakas_2000, Dalakas_2003). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Dalakas_2003, Mavrodis_2008). One study reported that this variant was functional and normally interacted with other intermediate filaments (Dalakas_2003) while another reported that mutant desmin loses its Z-disc localization but it can still associate with the intercalated discs, which, however, have an altered architecture, resembling other examples of dilated cardiomyopathy (Mavrodis_2008). These results however, do not allow convincing conclusions about the variant effect. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2020

The c.1353C>G (p.I451M) alteration is located in exon 8 (coding exon 8) of the DES gene. This alteration results from a C to G substitution at nucleotide position 1353, causing the isoleucine (I) at amino acid position 451 to be replaced by a methionine (M). 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	Pathogenic	0.59
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	9.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	0.69	N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.85
MVP		0.96
MPC		1.4
ClinPred		0.60	D
GERP RS		-7.4
Varity_R		0.24
gMVP		0.89

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: rs121913002; hg19: chr2-220290449;