Submissions for variant NM_005572.4(LMNA):c.1711C>A (p.Arg571Ser)

dbSNP: rs80338938

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000705473	SCV000834472	pathogenic	Charcot-Marie-Tooth disease type 2	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 10 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. This variant is present in population databases (rs80338938, gnomAD 0.01%). This variant has been observed in individual(s) with dilated cardiomyopathy and conduction defects and/or lipodystrophy (PMID: 10580070, 28686329). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1711C>A (p.Arg571Ser). ClinVar contains an entry for this variant (Variation ID: 14485). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001189216	SCV001356461	uncertain significance	Cardiomyopathy	2023-10-16	criteria provided, single submitter	clinical testing	This missense variant (p.Arg571Ser; c.1711C>A) occurs 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+13C>A in lamin A transcript (NM_170707.3). Computational prediction tools indicate that this missense variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy and conduction system disease in one large multigenerational family (PMID: 10580070). Five carriers were affected with rhythm disturbance and three carriers were affected with both rhythm disturbance and dilated cardiomyopathy. Three unaffected carriers were under age 30. Affected individuals in this family showed mild cardiac phenotype and lacked skeletal-muscle symptoms. A different variant causing the same protein effect (c.1711_1712delinsTC; p.Arg571Ser) has been reported in two individuals affected with juvenile-onset generalized lipodystrophy in one family (PMID: 28686329). This variant has been identified in 5/150320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000057044	SCV001985353	uncertain significance	not provided	2019-11-25	criteria provided, single submitter	clinical testing	Identified using alternate nomenclature R571S in a single family with variable cardiac conduction system disease, atrial fibrillation, dilated cardiomyopathy, and elevated creatine kinase without symptoms of muscular dystrophy, however, only the LMNA gene was sequenced, and in vitro functional studies were not included (Fatkin et al., 1999); In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10580070)
AiLife Diagnostics, AiLife Diagnostics	RCV000057044	SCV002502444	uncertain significance	not provided	2021-09-29	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993745	SCV004812647	likely pathogenic	Primary dilated cardiomyopathy	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change in LMNA is predicted to replace arginine with serine at codon 571 in a lamin C-specific residue, p.(Arg571Ser). The variant is non-coding in the lamin A transcript (NM_170707.4:c.1698+13C>A). The arginine residue is located in the lamin C tail domain (PMID: 8344919). There is a large physicochemical difference between arginine and serine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.007% (4/57,466 alleles) in the European (non-Finnish) population. This variant has been reported in at least one proband with atrial fibrillation (PMID: 23483212). The missense variant (without the underlying nucleotide description) has been reported in an individual with a phenotype consistent with Emery-Dreifuss Muscular Dystrophy (PMID: 23483212). The variant has been reported to segregate with atrial fibrillation and/or dilated cardiomyopathy in a large multigenerational family (PMID:10580070). The variant hindered myogenic differentiation (cell fusion and myotube formation) in in vitro assays in mouse cells indicating that this variant impacts protein function (PMID: 30199159). Computational evidence is uninformative for the missense substitution (REVEL = 0.485) and no impact on splicing is predicted for the variant (SpliceAI). The same amino acid change (p.Arg571Ser), resulting from a different nucleotide change c.1711_1712delinsTC, has been reported in siblings with generalised lipodystrophy (PMID: 28686329). The variant has been reported as likely pathogenic/pathogenic previously (ClinVar, Shariant). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PM2_Supporting, PS3_Supporting.
Ambry Genetics	RCV004018634	SCV005030790	uncertain significance	Cardiovascular phenotype	2023-11-06	criteria provided, single submitter	clinical testing	The c.1698+13C>A intronic variant results from a C to A substitution 13 nucleotides after coding exon 10 in the LMNA gene. In an alternate isoform, this variant results in a missense change (NM_005572:c.1711C>A, p.R571S) which has been detected in affected individuals from a family with dilated cardiomyopathy and cardiac arrhythmia, and in additional individuals with skeletal myopathy and cardiac arrhythmia (Fatkin D et al. N Engl J Med, 1999 Dec;341:1715-24; Ng KK et al. Australas Med J, 2013 Feb;6:75-8de Las Heras JI et al. Hum Mol Genet, 2023 Mar;32:1010-1031). This variant is not considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
OMIM	RCV000015574	SCV000035839	pathogenic	Dilated cardiomyopathy 1A	1999-12-02	no assertion criteria provided	literature only
GeneReviews	RCV000015574	SCV000041153	not provided	Dilated cardiomyopathy 1A		no assertion provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057044	SCV000088157	not provided	not provided		no assertion provided	not provided