ClinVar Miner

Submissions for variant NM_000109.4(DMD):c.1700T>C (p.Leu567Pro) (rs370644567)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000516302 SCV000226280 uncertain significance not provided 2017-12-26 criteria provided, single submitter clinical testing
GeneDx RCV000516302 SCV000235862 pathogenic not provided 2018-09-26 criteria provided, single submitter clinical testing The L575P variant in the DMD gene has been reported previously in three unrelated males withelevated CK, exertional myalgia, muscle stiffness, and myoglobinuria, two of whom had normaldystrophin immunostaining and Western blot analysis in muscle. Muscle biopsies showed abnormalmuscle histology (Veerapandiyan et al., 2010). Additionally, this variant has been observed in a malewith presumed Duchenne muscular dystrophy and elevated CK levels but with normal dystrophinstaining (Witt et al., 2017). Also, L575P has been observed at GeneDx in at least four unrelated maleswith elevated CK levels and muscular symptoms. The L575P variant is not observed at a significantfrequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015;Exome Variant Server). The L575P variant is a semi-conservative amino acid substitution, which mayimpact secondary protein structure as these residues differ in some properties. This substitution occursat a position that is conserved across species. In silico analysis predicts this variant is probablydamaging to the protein structure/function. In summary, we interpret L575P as a pathogenic variant.
Athena Diagnostics Inc 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)
Ambry Genetics RCV000622871 SCV000742950 likely pathogenic Inborn genetic diseases 2018-01-12 criteria provided, single submitter clinical testing
Invitae RCV000630575 SCV000751540 uncertain significance Duchenne muscular dystrophy 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 575 of the DMD protein (p.Leu575Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs370644567, ExAC 0.002%). This variant has been reported in several individuals affected with mild features of dystrophinopathy (PMID: 21104870). ClinVar contains an entry for this variant (Variation ID: 161220). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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.
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

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