rs370644567

Positions:

• chrX-32573618-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_004006.3(DMD):​c.1724T>C​(p.Leu575Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,209,011 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 3 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:10
• Conservation: PhyloP100: 7.71

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.1724T>C	p.Leu575Pro	missense_variant	15/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.1724T>C	p.Leu575Pro	missense_variant	15/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000623 AC: 7 AN: 112270 Hom.: 0 Cov.: 23 AF XY: 0.0000872 AC XY: 3 AN XY: 34422

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

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: 0.000113

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1096741 Hom.: 0 Cov.: 30 AF XY: 0.00000828 AC XY: 3 AN XY: 362159

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

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: 0.0000155

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000623 AC: 7 AN: 112270 Hom.: 0 Cov.: 23 AF XY: 0.0000872 AC XY: 3 AN XY: 34422

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000950

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00218 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; This variant is associated with the following publications: (PMID: 33644936, 25637381, 21104870) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 11, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2018	The best available variant frequency is uninformative because there are too few occurrences in population data. Statistically enriched in uncharacterized patients compared to unmatched population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in a known repetitive region of the protein. Statistically associated with disease in multiple families. (p < 0.05) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 26, 2017	- -

not specified Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 22, 2015	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. Given the suspicious case data and absence in unselected individuals we consider this variant a variant of uncertain significance, probably disease causing. The variant has been seen in at least 3-4 presumably unrelated individuals with elevated CKs and, in some cases, other signs of muscle disease. Veerapandiyan et al (2010) reported three unrelated boys with exertional myalgia, muscle stiffness, myoglobinuria and normal nuerological exam who all carried this variant. Two of the three boys had dystophin imunostaining and Western blot analysis of skeletal muscle, which was normal. All three had elevated CKs. Their phenotypes are summarized here: They specifically note that two of the boys had echos and ECGs, which were normal. The authors also report that the subjects had extensive work-ups for other causes of their phenotypes and that the variant is in the rod domain. They note that other rod domain variants have been associated with mild phenotypes like this. To the author’s knowledge these three individuals have not developed cardiomyopathy. They do get screening echos. The variant was reported online in the Leiden muscular dystrophy database in two individuals. No clinical data is provided for one. The other is noted to have recurrent rhabdomyolysis. In silico analysis with PolyPhen-2 predicts the variant to be damaging (0.998). The leucine at codon 575 is highly conserved across species. The variant was reported online in 1 of 43,652 individuals 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 September 16, 2015). Specifically, the variant was observed in 1 of 23,874 European individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2018	The DMD c.1724T>C; p.Leu575Pro variant (rs370644567), is reported in the literature in multiple individuals affected with dystrophinopathies (Veerapandiyan 2010). This variant is reported as uncertain significance/likely pathogenic/pathogenic in ClinVar (Variation ID: 161220), and is only observed on two alleles in the Genome Aggregation Database. The leucine at codon 575 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Leu575Pro variant is uncertain at this time. References: Veerapandiyan A et al. Pseudometabolic presentation of dystrophinopathy due to a missense mutation. Muscle Nerve. 2010 Dec;42(6):975-9. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Becker muscular dystrophy Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Mar 12, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 21, 2023	- -

Duchenne muscular dystrophy Pathogenic:1 Uncertain:1

Pathogenic, low penetrance, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 575 of the DMD protein (p.Leu575Pro). This variant is present in population databases (rs370644567, gnomAD 0.002%). This missense variant is significantly enriched in male individuals referred to Invitae for diagnostic genetic testing of muscular dystrophy and has been observed in individual(s) with mild features of dystrophinopathy as well as in some unaffected individuals (PMID: 21104870; Invitae). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 161220). 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 not expected to disrupt DMD protein function with a negative predictive value of 95%. In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the DMD gene, it has been classified as Pathogenic (low penetrance). -
Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Mar 12, 2019	- -

Qualitative or quantitative defects of dystrophin Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 13, 2023

Variant summary: DMD c.1724T>C (p.Leu575Pro) results in a non-conservative amino acid change located in the Central rod domain: Repeat 3 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 6.3e-05 in 111347 control chromosomes, including 3 hemizygotes (gnomAD v3.1.2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1724T>C has been reported in the literature in 3 unrelated boys who presented with exertional myalgia, rhabdomyolysis, and myoglobinuria without fixed muscle weakness or calf hypertrophy (Veerapandiyan_2010). It was also reported in an individual with clinical suspicion of DMD (Nallamilli_2021) and in individuals affected with dilated cardiomyopathy (Rieger_2019). More recently, the variant has been reported in several cases of Becker muscular dystrophy, many of which have a mild phenotype with reported exercise-induced myalgia and elevated creatine kinase levels; some of these individuals were also reported to have cognitive complications, including ADHD and autism (Becker_2021, Railean_2022, Tavallaee_2022). These data indicate that the variant is likely to be associated with disease, although individuals with the variant display a relatively mild/atypical phenotype. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments; six submitters classified the variant as uncertain significance, and four classified it as pathogenic/likely pathogenic. One of the submitters reports observations from internal testing of the variant being significantly enriched in male individuals referred for diagnostic genetic testing of muscular dystrophy, but also seen unaffected individual(s) (SCV000751540.6). Based on the evidence outlined above, the variant was classified as likely pathogenic for atypical phenotype of Dystrophinopathy, with potential incomplete penetrance. -

Exertional myalgia, muscle stiffness and myoglobinuria Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Dilated cardiomyopathy 3B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Counsyl

Mar 12, 2019

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2024

The p.L575P variant (also known as c.1724T>C), located in coding exon 15 of the DMD gene, results from a T to C substitution at nucleotide position 1724. The leucine at codon 575 is replaced by proline, an amino acid with similar properties. This variant has been detected in three pediatric-aged males with elevated serum CK and other signs of myopathy including exertional myalgia and abnormal muscle biopsies. However, dystrophin immunostaining and Western blot analyses were reportedly normal (Veerapandiyan A et al. Muscle Nerve, 2010 Dec;42:975-9). This variant (referred to as p.L567P, c.1700T>C) has been seen in an exome cohort, but clinical history was not provided (Amendola LM et al. Genome Res, 2015 Mar;25:305-15). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (1/22008) total alleles studied, with 0 hemizygotes observed. The highest observed frequency was <0.01% (1/10867) of European (non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;.;D;D;D;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;.;D;.
Vest4		0.94
MVP		0.99
MPC		0.13
ClinPred		0.97	D
GERP RS		5.2
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370644567; hg19: chrX-32591735;