ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1007G>A (p.Arg336Gln)

gnomAD frequency: 0.00003  dbSNP: rs58105277
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000225878 SCV000291541 pathogenic Charcot-Marie-Tooth disease type 2 2024-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 336 of the LMNA protein (p.Arg336Gln). This variant is present in population databases (rs58105277, gnomAD 0.01%). This missense change has been observed in individuals with Emery-Dreifuss muscular dystrophy and dilated cardiomyopathy (PMID: 29693488). ClinVar contains an entry for this variant (Variation ID: 66758). 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 expected to disrupt LMNA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002426615 SCV002728887 uncertain significance Cardiovascular phenotype 2024-11-20 criteria provided, single submitter clinical testing The p.R336Q variant (also known as c.1007G>A), located in coding exon 6 of the LMNA gene, results from a G to A substitution at nucleotide position 1007. The arginine at codon 336 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in multiple patients with Emery-Dreifuss muscular dystrophy, but was also detected in several unaffected individuals (Raffaele Di Barletta M et al. Am. J. Hum. Genet., 2000 Apr;66:1407-12; Sanna T et al. Eur. Heart J., 2003 Dec;24:2227-36; Peretto G et al. Ann. Intern. Med., 2019 10;171:458-463; Bernasconi P et al. Nucleus, 2018 01;9:292-304; Park J et al. Genet. Med., 2020 01;22:102-111). 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.
Athena Diagnostics RCV000057214 SCV002771304 uncertain significance not provided 2021-12-21 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002483086 SCV002803245 uncertain significance Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2 2021-11-02 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000057214 SCV004698994 uncertain significance not provided 2023-12-01 criteria provided, single submitter clinical testing LMNA: PM1, PS4:Supporting
All of Us Research Program, National Institutes of Health RCV003996492 SCV004817549 uncertain significance Primary dilated cardiomyopathy 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 336 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Emery Dreifuss Muscular Dystrophy and cardiac involvement (PMID: 10739764, 14659775, 29693488). This variant has been identified in 7/250572 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.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057214 SCV000088327 not provided not provided no assertion provided not provided

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