rs5030730

Positions:

• chrX-32438372-G-A

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.3940C>T​(p.Arg1314Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1314R) has been classified as Likely benign. 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:10
• Conservation: PhyloP100: 3.30

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-32438372-G-A is Pathogenic according to our data. Variant chrX-32438372-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32438372-G-A is described in Lovd as [Pathogenic]. Variant chrX-32438372-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.3940C>T	p.Arg1314Ter	stop_gained	29/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.3940C>T	p.Arg1314Ter	stop_gained	29/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 10, 2018	The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2019	Reported in ClinVar as pathogenic (ClinVar Variant ID# 11283; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Immunohistochemical analysis of muscle biopsy showed reduced dystrophin for antibodies to the N and C termini, but showed absent dystrophin for antibodies that corresponded to exon 29 (Ginjaar et al., 2000). RNA analysis of different probands with this variant revealed up to 3 transcripts: R1314X in exon 29, and 2 alternatively spliced versions missing either exon 29 or exons 28 and 29, which both bypass the nonsense variant (Ginjaar et al., 2000; Deburgrave et al., 2007). Furthermore, the truncated protein was visible by Western blot (Ginjaar et al., 2000); Other nonsense variants in DMD have been reported in the Human Gene Mutation Database in association with dystrophimopathies (Stenson et al., 2014); Based on the understanding of this genetic alteration, it may be amenable to nonsense read-through therapy that is currently available or in clinical trial; This variant is associated with the following publications: (PMID: 28116794, 17041906, 25525159, 11039581, 16770791, 19959795, 25972034, 30833962, 29604111, 29581631) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2017	- -

Duchenne muscular dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 24, 2021	Studies have shown that this variant is associated with skipping of exon 29 but is expected to preserve the integrity of the reading frame (PMID: 11039581, 17041906, 24292997). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in several individuals and families affected with Becker muscular dystrophy (PMID: 11039581, 17041906, 19959795, 24292997, 29581631). ClinVar contains an entry for this variant (Variation ID: 11283). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg1314*) in the DMD gene. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Qualitative or quantitative defects of dystrophin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 28, 2023

Variant summary: DMD c.3940C>T (p.Arg1314X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 182875 control chromosomes (gnomAD). c.3940C>T has been reported in the literature in multiple hemizygous males affected with Becker Muscular Dystrophy, dilated cardiomyopathy, and elevated serum creatine kinase levels (e.g., Franz_2000, Ginjaar_2000, Deburgrave_2007, Torella_2010), and the variant has been shown to segregate with disease in related individuals. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein, finding that alternative exon skipping restored the open reading frame in a portion of transcripts in patient tissue, however, the level of exon skipping varied across tissues and between patients, correlating with disease severity and phenotypic outcomes (e.g., Franz_2000, Ginjaar_2000, Deburgrave_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17041906, 10832829, 11039581, 19959795). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Becker muscular dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.92
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs5030730; hg19: chrX-32456489; COSMIC: COSV63740877;