Submissions for variant NM_170707.4(LMNA):c.1004G>A (p.Arg335Gln)

gnomAD frequency: 0.00006  dbSNP: rs138592977

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727308	SCV000293396	likely pathogenic	not provided	2023-08-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that cardiomyocytes harboring the p.R335Q variant have abnormal sarcomere architecture, increased ERK signaling, and deregulated Ca2+ signaling, while cardiac fibroblasts have decreased GJA1 expression, nuclear circularity, and migration rates (Yang et al., 2021); This variant is associated with the following publications: (PMID: 28790152, 23062543, 31514951, 32041611, 34862408, 10939567, 32413188, 28416588, 34975533, 30847666, 28663758, 31744510)
Eurofins Ntd Llc (ga)	RCV000727308	SCV000707459	uncertain significance	not provided	2017-04-05	criteria provided, single submitter	clinical testing
Invitae	RCV000653901	SCV000775791	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 335 of the LMNA protein (p.Arg335Gln). This variant is present in population databases (rs138592977, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 23062543, 28416588, 28790152, 34975533). ClinVar contains an entry for this variant (Variation ID: 246074). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 34862408, 34975533). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000771975	SCV000904929	uncertain significance	Cardiomyopathy	2023-11-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 335 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 23062543, 28416588, 34975533). This variant has also been identified in 20/281664 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at this codon (p.Arg335Trp) is considered to be pathogenic (Clinvar variation ID 36473), suggesting that arginine at this amino acid position is important for the protein function. However, due to the observations in the general population and limited reports of affected carriers, 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.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001174248	SCV001337378	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002401922	SCV002713701	uncertain significance	Cardiovascular phenotype	2023-07-11	criteria provided, single submitter	clinical testing	The p.R335Q variant (also known as c.1004G>A), located in coding exon 6 of the LMNA gene, results from a G to A substitution at nucleotide position 1004. The arginine at codon 335 is replaced by glutamine, an amino acid with highly similar properties, and is located in the coil 2 domain. This alteration has been reported in individuals from dilated cardiomyopathy (DCM) and non-compaction cardiomyopathy cohorts; however, clinical detail was limited and case reports may overlap (Narula N et al. J. Am. Coll. Cardiol., 2012 Nov;60:1916-20; Dal Ferro M et al. Heart., 2017 Nov;103(21):1704-1710; Ditaranto R et al. Orphanet J Rare Dis. 2019 11;14(1):263; van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003998912	SCV004817087	uncertain significance	Primary dilated cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 335 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 23062543, 28416588, 34975533). This variant has also been identified in 20/281664 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at this codon (p.Arg335Trp) is considered to be pathogenic (Clinvar variation ID 36473), suggesting that arginine at this amino acid position is important for the protein function. However, due to the observations in the general population and limited reports of affected carriers, 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.
Clinical Genetics, Academic Medical Center	RCV000727308	SCV002034536	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000727308	SCV002037402	uncertain significance	not provided		no assertion criteria provided	clinical testing