Submissions for variant NM_005572.4(LMNA):c.1711_1712delinsTC (p.Arg571Ser)

dbSNP: rs794728612

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000725840	SCV000234734	uncertain significance	not provided	2017-03-24	criteria provided, single submitter	clinical testing	The c.1711_1712delCGinsTC variant in the LMNA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1711_1712delCGinsTC variant results in a deletion of CG and insertion of TC, maintaining the reading frame and leading to an Arginine residue being replaced with a Serine residue at residue 571, denoted p.Arg571Ser. This 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 that is conserved in mammals. This variant is located within the globular caboxy-terminal tail domain (Bonne et al., 2000). The c.1711_1712delCGinsTC variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1711_1712delCGinsTC as a variant of uncertain significance.
Ambry Genetics	RCV000249124	SCV000318876	uncertain significance	Cardiovascular phenotype	2013-06-26	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Eurofins Ntd Llc (ga)	RCV000725840	SCV000339877	uncertain significance	not provided	2016-04-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001191556	SCV001359418	uncertain significance	Cardiomyopathy	2023-09-05	criteria provided, single submitter	clinical testing	This variant deletes and inserts two nucleotides, resulting in replacing arginine with serine at codon 571 at the C-terminal end of the lamin C protein (NM_005572.3) encoded by the LMNA gene, and corresponds to intronic position c.1698+13_1698+14delinsTC in lamin A (NM_170707.3). Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals in one family affected with juvenile-onset generalized lipodystrophy (PMID: 28686329). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant causing the same protein effect (c.1711C>A, p.Arg571Ser) has been reported in multiple individuals affected with dilated cardiomyopathy in one family (PMID: 10580070; ClinVar Variation ID: 14485). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001300467	SCV001489608	pathogenic	Charcot-Marie-Tooth disease type 2	2021-12-07	criteria provided, single submitter	clinical testing	The LMNA gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_005572.4, and corresponds to NM_170707.3:c.1698+13_1698+14delinsTC in the primary transcript. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 571 of the LMNA protein (p.Arg571Ser). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individuals with clinical features of autosomal dominant LMNA-related conditions (PMID: 10580070, 28686329; Invitae). ClinVar contains an entry for this variant (Variation ID: 200963). Studies have shown that this missense change does not affect mRNA splicing (PMID: 28686329). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003333038	SCV004041189	uncertain significance	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome	2023-02-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528958	SCV004108646	uncertain significance	LMNA-related disorder	2023-03-31	criteria provided, single submitter	clinical testing	The LMNA c.1711_1712delinsTC variant is predicted to result in an in-frame deletion and insertion. Of note, this variant could also be referred to as c.1698+13_1698+14delinsTC with transcript NM_170707.2 and is not predicted to significantly alter splicing (Alamut Visual Plus v1.6.1). This variant was reported in two siblings with lipodystrophy and the deceased father had similar clinical features (Patni et al. 2017. PubMed ID: 28686329). In this study, no effect on mRNA splicing or lamin A or C mRNA or protein expression was observed in patient lymphoblasts. The same amino acid change (c.1711C>A, p.Arg571Ser) was also reported in 8 affected family members with dilated cardiomyopathy and conduction-system disease, but also detected in 3 asymptomatic family members who were all under 30 years of age (Fatkin D et al 1999. PubMed ID: 10580070). The p.Arg571Ser was recently reported in another patient with limb-girdle weakness and functional analysis indicated that multiple pathways were altered in cells from this patient (De Las Heras et al. 2023. PubMed ID: 36282542). At PreventionGenetics, we have observed the c.1711_1712delinsTC in a patient with hypotonia and respiratory difficulties. but it was found to be inherited from a presumably asymptomatic father (internal data). A different amino acid change at this position (p.Arg571Cys) has also been reported in many individuals with clinical features of laminopathy, but this variant is also reported in gnomAD (Benedetti et al. 2005. PubMed ID: 15965218; Magagnotti. 2012. PubMed ID: 22326558; Li et al. 2020. PubMed ID: 31521807; https://variantcentral/variant/236156). To our knowledge, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant could be contributing to varied laminopathy phenotypes, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.