rs863224999

Positions:

• chrX-32380626-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.4729C>T​(p.Arg1577Ter) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: DMD NM_004006.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.43

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-32380626-G-A is Pathogenic according to our data. Variant chrX-32380626-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32380626-G-A is described in Lovd as [Pathogenic]. Variant chrX-32380626-G-A is described in Lovd as [Benign]. Variant chrX-32380626-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.4729C>T	p.Arg1577Ter	stop_gained	34/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.4729C>T	p.Arg1577Ter	stop_gained	34/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 28, 2020	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; 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: 19783145, 21515508, 21972111, 28503591, 12233050, 20485447, 19937601, 25525159, 23453023, 18652600, 26110187, 28332368, 28318817, 31412794, 32559196, 34297739, 34925456) -

Duchenne muscular dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 26, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217199). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (PMID: 18652600, 19783145, 20485447, 21515508, 23453023). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1577*) 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	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Dec 16, 2022	PVS1, PM2, PP5 -

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

Oct 17, 2019

Variant summary: DMD c.4729C>T (p.Arg1577X) 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. The variant was absent in 182057 control chromosomes (gnomAD). c.4729C>T has been reported in the literature in multiple individuals affected with Dystrophinopathies. Most of these individuals were affected with DMD (Duchenne Muscular Dystrophy)(e.g. Esterhuizen_2014, Flanigan_2011, Takeshima_2010) .These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dilated cardiomyopathy 3B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Apr 06, 2023

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2020

The p.R1577* pathogenic mutation (also known as c.4729C>T), located in coding exon 34 of the DMD gene, results from a C to T substitution at nucleotide position 4729. This changes the amino acid from an arginine to a stop codon within coding exon 34. This alteration has been reported in multiple individuals with Duchenne muscular dystrophy (DMD) (Takeshima Y et al. J. Hum. Genet., 2010 Jun;55:379-88; Sedlácková J et al. Neuromuscul. Disord., 2009 Nov;19:749-53; Yang J et al. BMC Med. Genet., 2013 Mar;14:29; Mah JK et al. Can J Neurol Sci, 2011 May;38:465-74; Suh MR et al. Yonsei Med. J., 2017 May;58:613-618; Vieitez I et al. Neurologia Mar;32:377-385; Kong X et al. BMC Med. Genet., 2019 08;20:139; Flanigan KM et al. Hum. Mutat., 2009 Dec;30:1657-66). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A
Vest4		0.99
GERP RS		4.5

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: rs863224999; hg19: chrX-32398743; COSMIC: COSV63775138;