2-219420939-G-C

Variant names:

• chr2-219420939-G-C
• rs59962885
• NM_001927.4:c.1009G>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001927.4(DES):​c.1009G>C​(p.Ala337Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A337T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 6.20

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 11 ACMG points.

• PM1: In a region_of_interest Interaction with NEB (size 147) in uniprot entity DESM_HUMAN there are 50 pathogenic changes around while only 2 benign (96%) in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-219420939-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 2-219420939-G-C is Pathogenic according to our data. Variant chr2-219420939-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16820.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, not_provided=1}. Variant chr2-219420939-G-C is described in Lovd as [Pathogenic]. Variant chr2-219420939-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4	c.1009G>C	p.Ala337Pro	missense_variant	Exon 5 of 9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.1009G>C	p.Ala337Pro	missense_variant	Exon 5 of 9	1	NM_001927.4	ENSP00000363071.3
DES	ENST00000477226.6	n.483G>C		non_coding_transcript_exon_variant	Exon 4 of 8	4
DES	ENST00000492726.1	n.404G>C		non_coding_transcript_exon_variant	Exon 4 of 6	4
DES	ENST00000683013.1	n.397G>C		non_coding_transcript_exon_variant	Exon 3 of 7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Desmin-related myofibrillar myopathy Pathogenic:2 Uncertain:1

Jul 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 337 of the DES protein (p.Ala337Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with DES-related conditions (PMID: 9697706, 17199740, 33478057, 34418069). ClinVar contains an entry for this variant (Variation ID: 16820). 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 80%. Experimental studies have shown that this missense change affects DES function (PMID: 23530264, 33478057). 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. -

Jan 02, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DES c.1009G>C (p.Ala337Pro) results in a non-conservative amino acid change located in the 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 was absent in 250286 control chromosomes (gnomAD). c.1009G>C has been reported in the literature in heterozygous state in multiple families, in individuals affected with Desmin-related myofibrillar myopathy and cardiac involvement (e.g. Goldfarb_1998, Goudeau_2006, Kulikova_2021). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in abnormal cytoplasmic aggregate formation in the majority of transfected cells (e.g. Goudeau_2006, Kulikova_2021). The following publications have been ascertained in the context of this evaluation (PMID: 9697706, 16865695, 33478057). ClinVar contains an entry for this variant (Variation ID: 16820). Based on the evidence outlined above, the variant was classified as pathogenic for autosomal dominant myofibrillar myopathy and cardiac involvement. -

Aug 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1 Other:1

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DES: PM1, PM2, PP1:Moderate, PS3:Moderate, PS4:Moderate -

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dilated cardiomyopathy 1I Pathogenic:1

Nov 18, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1009G>C variant has been previously reported in association with skeletal myopathy with familial segregation (PMID: 9697706), and it has a very low frequency (rs59962885). Clinvar has an entry for this variant (Variation ID:16820). Functional study of the variant shows disruptive effect of proline in helical structure of the protein which leads to a loss of normal function (PMID: 16865695). Based on this evidences the c.1009G>C is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.84
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.87		Gain of catalytic residue at A337 (P = 0.0242);
MVP		0.99
MPC		1.7
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.93

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: rs59962885; hg19: chr2-220285661;