rs267607483

Positions:

• chr2-219420349-A-G
• chr2-219420349-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001927.4(DES):​c.735+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DES NM_001927.4 splice_region, intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 1.75

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219420349-A-G is Pathogenic according to our data. Variant chr2-219420349-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 66419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219420349-A-G is described in Lovd as [Pathogenic]. Variant chr2-219420349-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4	c.735+3A>G		splice_region_variant, intron_variant		ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.735+3A>G		splice_region_variant, intron_variant		1	NM_001927.4	ENSP00000363071.3
DES	ENST00000477226.6	n.209+3A>G		splice_region_variant, intron_variant		4
DES	ENST00000492726.1	n.130+3A>G		splice_region_variant, intron_variant		4
DES	ENST00000683013.1	n.123+3A>G		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2017	The c.735+3 A>G pathogenic variant in DES has been reported previously in the literature in association with desmin-related myopathy, cardiomyopathy, and limb-girdle muscular dytrophy (Dalakas et al., 2000; McDonald et al., 2012; Pugh et al., 2014; Walsh et al., 2017). Dalakas et al. (2000) identified this variant in a 50-year-old female with cardiomyopathy and muscle weakness and found it to be absent in her unaffected parents. In addition, McDonald et al. (2012) reported this variant to segregate with disease in a family who underwent whole exome sequencing for suspected limb-girdle muscular dystrophy. Five of the individuals in this family who harbored the c.735+3 A>G variant had cardiac involvement. Subsequently, Pugh et al. (2014) reported this variant in a 49-year-old female with a diagnosis of DCM with AV block, ventricular tachycardia and a family history of DCM and muscular dystrophy. In silico splice prediction programs predict this variant destroys or reduces the efficiency of the splice donor site in intron 3 and mRNA studies demonstrated that this variant results in the deletion of exon 3 (Dalakas et al., 2000). Other splice site variants, including one impacting the same splice donor site (c.735+1 G>A), have been reported in the DES gene in association with DES-related disorders (Stenson et al., 2014). Furthermore, the c.735+3 A>G variant is not observed in large population cohorts (Lek et al., 2016). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2017	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Desmin-related myofibrillar myopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 66419). This variant is also known as IVS3+3A>G. This variant has been observed in individual(s) with DES-related conditions (PMID: 10717012, 23155419, 24503780, 27532257). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This sequence change falls in intron 3 of the DES gene. It does not directly change the encoded amino acid sequence of the DES protein. It affects a nucleotide within the consensus splice site. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -

Primary dilated cardiomyopathy;C1832370:Desmin-related myofibrillar myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 10, 2014

The 735+3A>G variant in DES has been reported in 6 individuals with desmin myopa thy or limb-girdle muscular dystrophy with 1 de novo occurrence and was found t o segregate with disease in 9 affected individuals from 2 families (Park 2000, D alakas 2000, Wahni 2012, Greenberg 2012 , McDonald 2012, Gudkova 2013, LMM unpub lished data). This variant was absent from large population studies. The 735+3A> G variant is located in the 5' splice region. In vitro splicing studies indicate that this variant may result in the skipping of exon 3, resulting in an in-fram e deletion of 32 amino acids (Park 2000). Additional functional studies indicate this variant leads to abnormal aggregation of desmin fibers (Dalakas 2000, Park 2000). However, these types of assays may not accurately represent biological f unction. In summary, this variant meets our criteria to be classified as pathoge nic for desminopathy in an autosomal dominant manner (http://www.partners.org/pe rsonalizedmedicine/LMM) based upon de novo occurrence, segregation studies, abse nce from controls, and functional evidence. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2020

The c.735+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 3 in the DES gene. This variant (also reported as IVS3+3A>G) has been reported in individuals and families with desminopathy-related disease, whose findings have included cardiac arrhythmias, conduction defects, cardiomyopathies, and skeletal myopathies (Dalakas MC et al. N Engl J Med, 2000 Mar;342:770-80; Park KY et al. J Med Genet, 2000 Nov;37:851-7; McDonald KK et al. PLoS One, 2012 Nov;7:e48864; Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Stpie-Wojno M et al. Ann Noninvasive Electrocardiol, 2020 07;25:e12707). This mutation was found to occur as de novo in one of these families, and in another it showed segregation in affected family members (Park KY et al. J Med Genet, 2000 Nov;37:851-7; McDonald KK et al. PLoS One, 2012 Nov;7:e48864). RNA and immunofluorescence studies confirmed the deletion of exon 3 due to loss of the native splice donor site (Dalakas MC et al. N Engl J Med, 2000 Mar;342:770-80; Park KY et al. J Med Genet, 2000 Nov;37:851-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607483; hg19: chr2-220285071;