2-219418869-T-A

Position:

chr2-219418869-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The ENST00000373960.4(DES):c.407T>A(p.Leu136His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,574,354 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L136P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

DES
ENST00000373960.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 7.84

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a region_of_interest Coil 1A (size 32) in uniprot entity DESM_HUMAN there are 20 pathogenic changes around while only 1 benign (95%) in ENST00000373960.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-219418869-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265811.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4 linkuse as main transcript	c.407T>A	p.Leu136His	missense_variant	1/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4 linkuse as main transcript	c.407T>A	p.Leu136His	missense_variant	1/9	1	NM_001927.4	ENSP00000363071	P1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000550

AC:

AN:

181860

Hom.:

AF XY:

0.0000409

AC XY:

AN XY:

97680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

176

AN:

1422204

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

703820

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000523

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:

0.000156

Gnomad4 OTH exome

AF:

0.0000679

GnomAD4 genome

AF:

0.000125

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000183

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000591

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2023	Reported in association with cardiomyopathy, primary electrical disease, and neuromuscular disease (Pugh et al., 2014; Wilson et al., 2015; Proost et al., 2017; Campuzano et al., 2020; Gonzalez-Quereda L et al., 2020); 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: 32268277, 28341588, 30564623, 24503780, 32403337, 33823640, 30755392, 26265630, 36497166, 26807690) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2019	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DES: PM5 -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 18, 2013	The Leu136His variant in DES has been identified by our laboratory in 1 individu al with DCM (LMM unpublished data). Data from large population studies is insuff icient to assess the frequency of this variant. Leucine (Leu) at position 136 is conserved in mammals, but not in more evolutionarily distant species. However, other computational analyses (biochemical amino acid properties, AlignGVGD, Poly Phen2, and SIFT) suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. Additional infor mation is needed to fully assess the clinical significance of this variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 07, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below we consider this variant a variant of uncertain significance. This is a novel variant. This is a non-conservative amino acid change of a hydrophobic leucine to a hydrophilic histidine. The leucine at codon 136 is well conserved across evolution (except in chickens). PolyPhen2 predicts the variant to be probably damaging. Mutation Taster predicts this variant to be disease-causing. The leucine at codon 136 is conserved across species, as are neighboring amino acids. In total the variant has not been seen in ~6,700 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 136 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/30/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 9/30/13). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2023	Variant summary: DES c.407T>A (p.Leu136His) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 181860 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.407T>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy or Primary electrical disease (Pugh_2014, Wilson_2015, Proost_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. Seven ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Desmin-related myofibrillar myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 136 of the DES protein (p.Leu136His). This variant is present in population databases (rs397516695, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of DES-related conditions (PMID: 26265630, 28341588, 30755392, 32403337). ClinVar contains an entry for this variant (Variation ID: 44261). 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) performed at Invitae indicates that this missense variant is expected to disrupt DES protein function with a positive predictive value of 95%. 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. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 13, 2020

- -

Desmin-related myofibrillar myopathy;C1858154:Dilated cardiomyopathy 1I;C1867005:Neurogenic scapuloperoneal syndrome, Kaeser type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 07, 2022

- -

Myopathy;C0221629:Proximal muscle weakness;C0476273:Respiratory distress;C1533847:Skeletal myopathy;C1858120:Generalized hypotonia;C1866012:Proximal muscle weakness in upper limbs;C2267233:Neonatal hypotonia;C3277226:Restrictive ventilatory defect;C3806467:Respiratory insufficiency due to muscle weakness;C3806604:Infantile axial hypotonia;C4024967:Congenital peripheral neuropathy;C4281993:Neonatal respiratory distress;C5400698:Pulmonary alveolar proteinosis;C5441745:Abnormal pulmonary interstitial morphology

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.407T>A (p.L136H) alteration is located in exon 1 (coding exon 1) of the DES gene. This alteration results from a T to A substitution at nucleotide position 407, causing the leucine (L) at amino acid position 136 to be replaced by a histidine (H). 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

0.93

CardioboostCm

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.83

MutPred

0.80

Loss of MoRF binding (P = 0.1031);

MVP

0.98

MPC

2.3

ClinPred

0.99

GERP RS

4.7

Varity_R

0.94

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over