ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.83G>A (p.Arg28Gln)

dbSNP: rs886043109
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000380269 SCV000338492 likely pathogenic not provided 2018-08-15 criteria provided, single submitter clinical testing
Invitae RCV000809047 SCV000949184 pathogenic Charcot-Marie-Tooth disease type 2 2022-06-04 criteria provided, single submitter clinical testing This missense change has been observed in individuals with clinical features of autosomal dominant LMNA-related conditions (PMID: 20980393, 21632249; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 28 of the LMNA protein (p.Arg28Gln). ClinVar contains an entry for this variant (Variation ID: 285468). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg28 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12015247, 17711925). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Revvity Omics, Revvity Omics RCV000380269 SCV002022704 likely pathogenic not provided 2019-07-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298563 SCV002599027 likely pathogenic Benign scapuloperoneal muscular dystrophy with cardiomyopathy 2022-09-29 criteria provided, single submitter clinical testing Variant summary: LMNA c.83G>A (p.Arg28Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 223856 control chromosomes (gnomAD). c.83G>A has been reported in the literature in an individual diagnosed with limb-girdle muscular dystrophy, type 1B and in an individual affected with inflammatory myopathy (e.g. Mitsuhashi_2010, Komaki_2011). Other variants affecting the same amino acid residue (p.Arg28Gly, p.Arg28Trp) are cited in ClinVar and HGMD as pathogenic and disease-associated. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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