rs1064325

Positions:

• chrX-32345999-G-A
• chrX-32345999-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004006.3(DMD):​c.5530C>T​(p.Arg1844*) variant causes a stop gained 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DMD NM_004006.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.15

Genes affected

DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-32345999-G-A is Pathogenic according to our data. Variant chrX-32345999-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 94669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32345999-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.5530C>T	p.Arg1844*	stop_gained	39/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.5530C>T	p.Arg1844*	stop_gained	39/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Duchenne muscular dystrophy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Dec 16, 2022	PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Apr 23, 2020	A hemizygous nonsense variation in exon 39 of the DMD gene that results in a stop codon and premature truncation of the protein at codon 1844 was detected. The observed variant c.5530C>T (p.Arg1844Ter) has not been reported in the 1000 genomes and ExAC databases. The variant has previously been reported in a patient affected with Duchenne muscular dystrophy (Hofstra et al. 2004). The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 94669). This premature translational stop signal has been observed in individual(s) with Duchenne muscular dystrophy (PMID: 14695533, 16770791, 21396098, 23536893). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1844*) in the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained variant c.5530C>T (p.Arg1844Ter) in DMD gene has been reported previously in patients affected with Duchenne muscular dystrophy (Magri et al., 2011; Juan-Mateu et al., 2013) and has also been shown to have arisen de novo in an additional individual with Duchenne muscular dystrophy (Hofstra et al., 2004). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in DMD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 28, 2016	- -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 11, 2016	p.Arg1844* (c.5530C>T) in exon 39 of the DMD gene (NM_004006.2) Seen in our center in an adult male with dilated cardiomyopathy, without muscular dystrophy. Genetic testing consistent with mosaicism. Given the case data, type of variant, and rarity, we consider this variant very likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). It is well established that nonsense variants in DMD are pathogenic (Juan-Mateu et al 2015). Loss of function variants like this cause nearly all cases of Duchenne muscular dystrophy. Consistent with this, there are only 12 loss of function variants in DMD in the ExAC database. This is in contrast to the number of loss of function variants expected for the gene's size, 114. Thus, there is strong evidence that nonsense DMD variants are pathogenic. DMD variants have also been implicated in isolated dilated cardiomyopathy, without muscular dystrophy. Jeff Towbin's group reported combined LOD score of 4.33 across two kindreds with x-linked DCM and then later identified a missense variant in DMD in one of these kindreds. See Nakamura et al (2015) for recent review of DCM associated with DMD variants (Pharmaceuticals 2015, 8, 303-320; doi:10.3390/ph8020303). Per that review, most reported cases of DCM with DMD variants have had an early onset (teens) and progressive course. Nakamura notes that while some cases have overt and progressive heart failure others have a very mild DCM that is responsive to beta blockers and ACE inhibitors. Female carriers with more slowly progressive DCM in mid-life have been reported. Multiple cases have been reported with DCM and DMD variants with normal skeletal muscle dystrophin on western blotting and other histopathological analysis. Per the lab report: "This particular variant has been reported in multiple individuals with Duchenne muscular dystrophy (PMID: 21396098, 23536893) and has also been shown to have arisen de novo in an additional individual with Duchenne muscular dystrophy (PMID: 14695533)." In total the variant has not been seen in ~60,000 individuals from publicly available population datasets. There is no variation at codon 1844 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 11th, 2016). The average coverage at that site in ExAC is 40x. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2022	This variant is expected to result in the loss of a functional protein. This variant has been identified in individuals with clinical features of DMD including an apparent de novo case. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

May 12, 2020

- -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PVS1+PS4_Moderate+PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	41
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.96
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1064325; hg19: chrX-32364116; COSMIC: COSV63753245;