ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs201583907
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000041324 SCV000065017 uncertain significance not specified 2021-03-30 criteria provided, single submitter clinical testing The p.Gly523Arg variant in LMNA has been reported in 2 individual with dilated cardiomyopathy (Millat 2009 PMID: 19318026, Fichna 2018 PMID: 29970176), 1 individuals with limb-girdle muscular dystrophy (Magri 2015 PMID: 26404900), as well as 2 siblings presenting with features of COL6A2 related myopathy as well as Emery-Dreifuss muscular dystrophy (Chapon 2008, conference abstract only). In the family described by Chapon et al, the myopathy present in both sibs was believed to be due recessively inherited COL6A2 variants. The LMNA variant was present in one of the sibs as well as the father, who was clinically normal but showed dystrophic changes as well as mild deficit of collagen 6 fibers. Our laboratory has identified this variant in 1 individual with LVNC, conduction system disease and muscle weakness and 3 individuals with DCM (Pugh 2014 PMID: 24503780). This variant has also been identified in 0.01% (18/120474) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3.
GeneDx RCV000057323 SCV000234703 uncertain significance not provided 2021-07-08 criteria provided, single submitter clinical testing Observed in individuals with dilated cardiomyopathy (DCM), limb girdle muscular dystrophy (LGMD), and/or familial partial lipodystrophy, Dunnigan variety (FPLD2); however, familial segregation studies were not described (Millat et al., 2009; Millat et al., 2011; Pugh et al., 2014; Haas et al., 2015; Magri et al., 2015, Fichna et al., 2018, Park et al., 2020, Vasandani et al., 2020); Observed to segregate with DCM, conduction disease, and/or subtle right ventricular abnormalities in individuals from one family, but was also observed in unaffected individuals in this family (Hylind et al., 2019); Published functional studies demonstrate altered ability of LMNA protein to interact with 5% of its protein targets (Dittmer et al., 2014); nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID #48045; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 10939567, 20074070, 27535533, 24623722, 32193531, 31383942, 30919684, 31744510, 29970176, 26633542, 27576561, 28679633, 28663758, 19318026, 25163546, 26404900, 21846512, 24846508, 24503780, 24375749)
Ambry Genetics RCV000245950 SCV000320458 uncertain significance Cardiovascular phenotype 2020-01-08 criteria provided, single submitter clinical testing The p.G523R variant (also known as c.1567G>A), located in coding exon 9 of the LMNA gene, results from a G to A substitution at nucleotide position 1567. The glycine at codon 523 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported as heterozygous in individuals with dilated cardiomyopathy (DCM) (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Millat G et al. Clin. Biochem., 2009 Jun;42:892-8; Millat G et al. Eur J Med Genet Aug;54:e570-5) and in individuals with limb girdle muscular dystrophy (LGMD) (Magri F et al. BMC Neurol, 2015 Sep;15:172; Fichna JP et al. Hum. Genomics, 2018 07;12:34). 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.
Eurofins NTD LLC (GA) RCV000057323 SCV000336479 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing
Invitae RCV000474372 SCV000548848 uncertain significance Charcot-Marie-Tooth disease type 2 2021-12-01 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 523 of the LMNA protein (p.Gly523Arg). This variant is present in population databases (rs201583907, gnomAD 0.01%). This missense change has been observed in individual(s) with limb girdle muscular dystrophy, dilated cardiomyopathy, or dyslipidemias (PMID: 19318026, 24503780, 26404900, 29970176, 32041611). ClinVar contains an entry for this variant (Variation ID: 48045). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 24623722). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
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
Color Diagnostics, LLC DBA Color Health RCV001181346 SCV001346472 uncertain significance Cardiomyopathy 2020-12-04 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 523 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study using a yeast two hybrid system has shown that this variant may lead to ~5% lost protein interactions (PMID: 24623722), but functional and clinical significance of this observation is not known . This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19318026, 21846512, 24503780, 29961767) and in an individual affected with limb girdle muscular dystrophy (PMID: 26404900). This variant has been identified in four members of one family (PMID: 30919684). One carrier from this family had subtle right ventricular abnormalities and her 2 children showed no cardiac phenotype, although her father had dilated cardiomyopathy and conduction disease. This variant has been identified in 22/264998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Johns Hopkins Genomics, Johns Hopkins University RCV001250579 SCV001425445 uncertain significance Dilated cardiomyopathy 1A 2020-02-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV001330499 SCV001522189 uncertain significance Lethal tight skin contracture syndrome 2019-06-21 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057323 SCV000088436 not provided not provided no assertion provided not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000057323 SCV001743354 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000057323 SCV001807449 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000057323 SCV001918068 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000057323 SCV001931676 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000057323 SCV001954184 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000057323 SCV001963796 uncertain significance not provided no assertion criteria provided clinical testing

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