Submissions for variant NM_170707.4(LMNA):c.1621C>A (p.Arg541Ser)

dbSNP: rs56984562

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823221	SCV000964072	pathogenic	Charcot-Marie-Tooth disease type 2	2022-10-13	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg541 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14684700, 18564364, 18646565, 23183350, 27532257). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 16061563, 16218190). 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. ClinVar contains an entry for this variant (Variation ID: 66859). This missense change has been observed in individual(s) with dilated cardiomyopathy or limb-girdle muscular dystrophy (PMID: 16061563, 16537768, 20848652, 31498906). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 541 of the LMNA protein (p.Arg541Ser).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017361	SCV004848636	likely pathogenic	Primary dilated cardiomyopathy	2011-10-07	criteria provided, single submitter	clinical testing	The Arg541Ser variant has been identified in at least 3 inidiviuals with DCM and was absent from 500 control chromosomes (Sylvuis 2005, Karkkainen 2006, Gupta 2010, Scharner 2011). One of these inidividuals was reported to have de novo occurance of this variant but no reference to ruling out non-medical explantations such as undisclosed adoption or non-paternity was mentioned in this article (Karkkainen 2006). In addition, this variant was reported in an individual with DCM but a family history of LGMD and DCM (Scharner 2011). Arginine (Arg) at position 541 is highly conserved across envolutionarily distant species, suggesting that a change may not be tolerated. Computational analysis (AlignGVGD, PolyPhen2, and SIFT) suggest that a change to a serine (Ser) at this position may impact the protien; however, the accuracy of such tools is unknown. In addition, changes to different amino acids at this position have been identified in individuals with muscular dystrophy (Arg541His, Arg541Pro) and DCM (Arg541Cys). Based on this information, the Arg541Ser variant is likely to be pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057341	SCV000088454	not provided	not provided		no assertion provided	not provided