Submissions for variant NM_170707.4(LMNA):c.184C>G (p.Arg62Gly)

dbSNP: rs56793579

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000503031	SCV000595595	pathogenic	Familial partial lipodystrophy, Dunnigan type	2016-06-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000503031	SCV000917595	pathogenic	Familial partial lipodystrophy, Dunnigan type	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.184C>G (p.Arg62Gly) results in a non-conservative amino acid change located in the intermediate filament, rod domain (IPR039008) of 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 226256 control chromosomes (gnomAD). c.184C>G has been reported in the literature in multiple individuals affected with Familial Partial Lipodystrophy-Dunnigan Type (examples: Garg_2002, Haque_2002, Subramanyan_2010, and Vasandani_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12015247, 12647844, 20041886, 36397776). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001051802	SCV001215980	pathogenic	Charcot-Marie-Tooth disease type 2	2022-07-11	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg62 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 16809772). 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. ClinVar contains an entry for this variant (Variation ID: 66868). This missense change has been observed in individual(s) with autosomal dominant LMNA-related conditions (PMID: 12015247). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 62 of the LMNA protein (p.Arg62Gly).
Athena Diagnostics Inc	RCV000057365	SCV002771302	pathogenic	not provided	2022-06-29	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant associates with familial partial lipodystrophy in multiple families. Computational tools predict that this variant is damaging.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057365	SCV000088478	not provided	not provided		no assertion provided	not provided