Submissions for variant NM_170707.4(LMNA):c.1081G>C (p.Glu361Gln)

dbSNP: rs267607634

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236290	SCV000293168	uncertain significance	not provided	2015-09-18	criteria provided, single submitter	clinical testing	The E361Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different missense variant at the same residue (E361K) has been reported in the literature. The E361K variant was identified in one individual who was diagnosed at 12 years-old with Emery-Dreifuss muscular dystrophy due to contractures of her ankle, achilles tendon, and elbow (Scharner et al., 2011). Although the proband had no cardiac involvement, her mother had a history of cardiomyopathy and heart transplant (Scharner et al., 2011); however, the mother's carrier status was not provided.The E361Q variant 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 E361Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where only amino acids with similar properties to Glutamic acid are tolerated across species. In addition, missense variants in nearby residues (Q353R, D357H, D357A, E358K, M371K) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), further supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208634	SCV001380033	likely pathogenic	Charcot-Marie-Tooth disease type 2	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 361 of the LMNA protein (p.Glu361Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of arrhythmogenic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 245948). 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%. This variant disrupts the p.Glu361 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16218190, 20848652; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.