Submissions for variant NM_170707.4(LMNA):c.1444C>T (p.Arg482Trp) (rs57920071)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory,University of Chicago	RCV000015579	SCV000247852	pathogenic	Familial partial lipodystrophy 2	2014-11-14	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001174239	SCV001337368	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Invitae	RCV001235764	SCV001408468	pathogenic	Charcot-Marie-Tooth disease, type 2	2019-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 482 of the LMNA protein (p.Arg482Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with familial partial lipodystrophy and was observed to segregate with disease in a family (PMID: 19622949, 25885670). ClinVar contains an entry for this variant (Variation ID: 14489). This variant has been reported to affect LMNA protein function (PMID: 19220582). This variant disrupts the p.Arg482 amino acid residue in LMNA. Other variant(s) that disrupt this residue (p.Arg482Gln) have been determined to be pathogenic (PMID: 10587585, 10999791, 19418082, 19859838, 20130076, 20625965, 26662654). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266075	SCV001444247	pathogenic	Inborn genetic diseases	2018-12-10	criteria provided, single submitter	clinical testing
OMIM	RCV000015579	SCV000035844	pathogenic	Familial partial lipodystrophy 2	2001-05-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057298	SCV000088411	not provided	not provided		no assertion provided	not provided
Broad Institute Rare Disease Group,Broad Institute	RCV001248961	SCV001422760	pathogenic	Familial partial lipodystrophy	2020-01-22	no assertion criteria provided	curation	The p.Arg482Trp variant in LMNA has been reported in at least 12 European individuals with familial partial lipodystrophy, segregated with disease in at least 7 affected relatives from 2 families (PMID: 15531479, 10655060,11344241), and has been identified in 0.0009% (1/113640) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs57920071). This variant has also been reported in ClinVar as pathogenic (Variation ID: 14489). In vitro functional studies provide some evidence that the p.Arg482Trp variant may slightly impact protein function (PMID: 25524705). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic and one pathogenic variant, resulting in a different amino acid change at the same position, p.Arg482Leu and p.Arg482Gln, have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 10655060, 14597414, 19201734, 23313286, 10587585, 20130076, 28492532 /Variation ID: 14490 and 14486). In summary, this variant meets criteria to be classified as pathogenic for familial partial lipodystrophy in an autosomal dominant manner based on cosegregation with disease in multiple affected families and the prevalence of this variant in many affected individuals. ACMG/AMP Criteria applied: PP1_strong, PS4_moderate, PM5, PM2, PP3, PS3_supporting (Richards 2015).