Submissions for variant NM_004006.3(DMD):c.1724T>C (p.Leu575Pro)

gnomAD frequency: 0.00006  dbSNP: rs370644567

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000516302	SCV000226280	uncertain significance	not provided	2017-12-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000516302	SCV000235862	pathogenic	not provided	2024-11-09	criteria provided, single submitter	clinical testing	Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 21104870, 33644936)
Athena Diagnostics	RCV000516302	SCV000613109	likely pathogenic	not provided	2018-12-31	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630575	SCV000751540	pathogenic, low penetrance	Duchenne muscular dystrophy	2025-02-02	criteria provided, single submitter	clinical testing	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 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; internal data). This missense change has been observed to be homozygous, hemizygous or homoplasmic in an individual who did not have the expected clinical features for that genetic result (internal data). ClinVar contains an entry for this variant (Variation ID: 161220). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000223816	SCV001157841	uncertain significance	not specified	2018-09-04	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003103987	SCV002050931	pathogenic	Qualitative or quantitative defects of dystrophin	2024-10-09	criteria provided, single submitter	clinical testing	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 was absent in 183132 control chromosomes. c.1724T>C has been reported in the literature in multiple individuals affected with Dystrophinopathies (example, (Becker_2021, Railean_2022, Tavallaee_2022, Herman_MN). 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. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 35135626, 33146414, 33644936, 31648988, 36409343, 26365249, 21104870, Railean et al). ClinVar contains an entry for this variant (Variation ID: 161220). Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000223816	SCV002516970	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408653	SCV002716656	uncertain significance	Cardiovascular phenotype	2024-05-09	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000516302	SCV003830049	uncertain significance	not provided	2019-09-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000984164	SCV004193993	likely pathogenic	Becker muscular dystrophy	2023-12-21	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786398	SCV005398330	pathogenic	Muscular dystrophy	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Becker muscular dystrophy (MIM#300376), Duchenne muscular dystrophy (MIM#310200) and dilated cardiomyopathy 3B (MIM#302045). (I) 0109 - This gene is associated with X-linked recessive disease. This gene is primarily associated with X-linked recessive disease relating to the muscular dystrophy phenotypes; however, it is also associated with X-linked DCM in heterozygous females (OMIM, GeneReviews, PMID: 26066469). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 v3 (6 heterozygotes, 0 homozygotes, 3 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Spectrin repeats superfamily domain (NCBI, UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant is predominantly reported to be associated with mild symptoms of muscular dystrophy and increased creatine kinase (CK) and has been reported in individuals with BMD, DMD, and non-ischemic DCM (ClinVar, LOVD, PMID’s: 36409343, 35135626, 33644936, 21104870, 31648988). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CSER _CC_NCGL, University of Washington	RCV000148464	SCV000190164	uncertain significance	Exertional myalgia, muscle stiffness and myoglobinuria	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223816	SCV000280073	uncertain significance	not specified	2015-09-22	no assertion criteria provided	clinical testing	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.
Counsyl	RCV000984164	SCV001132172	uncertain significance	Becker muscular dystrophy	2019-03-12	no assertion criteria provided	clinical testing
Counsyl	RCV000984165	SCV001132173	uncertain significance	Dilated cardiomyopathy 3B	2019-03-12	no assertion criteria provided	clinical testing
Counsyl	RCV000630575	SCV001132174	uncertain significance	Duchenne muscular dystrophy	2019-03-12	no assertion criteria provided	clinical testing