Submissions for variant NM_170707.4(LMNA):c.127G>A (p.Ala43Thr)

dbSNP: rs60446065

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057262	SCV000293392	likely pathogenic	not provided	2017-01-10	criteria provided, single submitter	clinical testing	The A43T variant has been reported previously in an individual with Emery-Dreifuss muscular dystrophy (EDMD) type 2 who was heterozygous for this change and did not have another identifiable LMNA variant; however, information about parental testing was not provided and functional characterization of the variant was not performed (Brown et al., 2001). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A43T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Eurofins Ntd Llc (ga)	RCV000057262	SCV000339872	uncertain significance	not provided	2018-04-03	criteria provided, single submitter	clinical testing
Invitae	RCV001225020	SCV001397255	pathogenic	Charcot-Marie-Tooth disease type 2	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 43 of the LMNA protein (p.Ala43Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of muscular dystrophy (PMID: 11503164; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66799). 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. Experimental studies have shown that this missense change affects LMNA function (PMID: 34862408). This variant disrupts the p.Ala43 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 28688748), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057262	SCV000088375	not provided	not provided		no assertion provided	not provided