ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1567G>A (p.Gly523Arg) (rs201583907)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000245950 SCV000320458 uncertain significance Cardiovascular phenotype 2015-11-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Insufficient or conflicting evidence
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678714 SCV000804881 likely pathogenic Left ventricular noncompaction 2017-04-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000057323 SCV000336479 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057323 SCV000088436 not provided not provided no assertion provided not provided
GeneDx RCV000041324 SCV000234703 uncertain significance not specified 2017-08-03 criteria provided, single submitter clinical testing The G523R variant in the LMNA gene has been previously reported in association with dilated cardiomyopathy (DCM) and Limb Girdle Muscular Dystrophy (LGMD); however, additional clinical information and familial segregation studies were not provided (Millat et al., 2009; Pugh et al., 2014; Haas et al., 2015; Magri et al., 2015). The G523R variant is observed in 7/38,488 alleles (0.02%) from individuals of non-Finnish European background in the ExAC dataset with no homozygous controls reported (Lek et al., 2016). The G523R variant results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A study of protein interaction found that G523R altered the ability of LMNA to interact with 5% of its targets, though the clinical validity of this observation was not established (Dittmer et al., 2014). Missense variants in nearby residues (W520R, W520G, W520S, R527C, R527P, R527L, and R527H) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Nonetheless, the G523R variant has been classified as a variant of uncertain significance by other clinical laboratories in ClinVar, one of which reports this variant was observed in two individuals with DCM who also harbored an additional likely pathogenic variant (SCV000065017.4, SCV000320458.1, SCV000336479.1; Landrum et al., 2016). In summary, this variant lacks observation in a sufficient number of affected individuals, segregation data, and functional evidence, all of which would further clarify pathogenicity. We therefore interpret G523R as a variant of uncertain significance.
Invitae RCV000474372 SCV000548848 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 523 of the LMNA protein (p.Gly523Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs201583907, ExAC 0.02%). This variant has been reported in the heterozygous state in 2 individuals affected with dilated cardiomyopathy (PMID: 19318026, 24503780) and in an individual affected with limb girdle muscular dystrophy (PMID: 26404900). ClinVar contains an entry for this variant (Variation ID: 48045). Experimental studies in a yeast two hybrid system show that this missense change leads to the loss of 4 interactions, but the functional significance of these observations is not known (PMID: 24623722). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041324 SCV000065017 uncertain significance not specified 2014-11-25 criteria provided, single submitter clinical testing The p.Gly523Arg variant in LMNA has been detected in 7/39252 European chromosome s screened by the Broad Institute (http://exac.broadinstitute.org/). It has als o been detected in individuals with features commonly caused by LMNA variants. T hese include 1 individual with DCM (Millat 2009) as well as two siblings present ing with features of COL6A2 related myopathy as well as EDMD (Chapon 2008, confe rence abstract only). In the family described by Chapon et al, the myopathy pres ent in both sibs was believed to be due recessively inherited Col2A6 variants. The LMNA variant was present in one of the sibs as well as the father, who was c linically normal but showed dystrophic changes as well as mild deficit of collag en 6 fibers. Our laboratory has identified this variant in 1 Caucasian individua l with LVNC, conduction system disease and muscle weakness and 2 Caucasian indiv iduals with DCM, both of whom carried an additional, likely pathogenic variant ( Pugh 2014). Computational prediction tools and conservation analysis suggest tha t the p.Gly523Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the available evidenc e for this variant is ambiguous and its clinical significance is uncertain.

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