ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.986G>A (p.Arg329His)

gnomAD frequency: 0.00002  dbSNP: rs397517913
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Total submissions: 7
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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 RCV000041377 SCV000065070 uncertain significance not specified 2012-12-06 criteria provided, single submitter clinical testing The Arg329His variant in LMNA has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stron g support for or against an impact to the protein. Additional information is nee ded to fully assess the clinical significance of this variant.
CSER _CC_NCGL, University of Washington RCV000590942 SCV000700102 uncertain significance Primary dilated cardiomyopathy 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of dilated cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color Diagnostics, LLC DBA Color Health RCV001181115 SCV001346201 uncertain significance Cardiomyopathy 2023-07-24 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 329 of the LMNA protein. 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 two individuals affected with dilated cardiomyopathy (PMID: 26468400, 29095976), one individual with unspecified cardiomyopathy (PMID 31383942), and one individual with conduction defect (PMID 31383942). This variant has been identified in 5/249996 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.
Invitae RCV001852843 SCV002280903 uncertain significance Charcot-Marie-Tooth disease type 2 2023-11-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 329 of the LMNA protein (p.Arg329His). This variant is present in population databases (rs397517913, gnomAD 0.004%). This missense change has been observed in individual(s) with LMNA-related conditions (PMID: 26468400, 29095976, 31383942). ClinVar contains an entry for this variant (Variation ID: 48091). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics RCV002477128 SCV002789745 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 2021-08-12 criteria provided, single submitter clinical testing
GeneDx RCV003226901 SCV003924008 uncertain significance not provided 2023-05-05 criteria provided, single submitter clinical testing Identified in a patient with DCM; however, detailed clinical information was not provided (Broch et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29095976, 10939567, 26468400)
Revvity Omics, Revvity RCV003226901 SCV004236253 uncertain significance not provided 2022-04-01 criteria provided, single submitter clinical testing

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