Submissions for variant NM_170707.4(LMNA):c.1001G>A (p.Ser334Asn)

gnomAD frequency: 0.00003  dbSNP: rs370656306

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726496	SCV000292720	uncertain significance	not provided	2022-09-08	criteria provided, single submitter	clinical testing	Identified in several unrelated patients with dilated cardiomyopathy, unspecified cardiomyopathy, or sudden cardiac death in published literature; however, no further clinical or segregation information was provided (van Spaendonck-Zwarts et al., 2013; van Lint et al., 2019; Verdonschot et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 10939567, 32880476, 23349452, 30847666)
Eurofins Ntd Llc (ga)	RCV000726496	SCV000701487	uncertain significance	not provided	2016-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000653909	SCV000775799	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 334 of the LMNA protein (p.Ser334Asn). This variant is present in population databases (rs370656306, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 23349452, 30847666, 32880476). ClinVar contains an entry for this variant (Variation ID: 161292). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LMNA protein function. 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	RCV001183553	SCV001349316	uncertain significance	Cardiomyopathy	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 334 of the lamin A/C protein. Computational prediction 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 at least 2 individuals affected with dilated cardiomyopathy (PMID: 23349452, 30847666, 32880476). It has also been reported in individuals affected with unspecified cardiomyopathy and aborted sudden cardiac death (PMID: 30847666). This variant has been identified in 6/281674 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.
Athena Diagnostics	RCV000726496	SCV001476533	uncertain significance	not provided	2019-09-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381457	SCV002693568	uncertain significance	Cardiovascular phenotype	2023-08-24	criteria provided, single submitter	clinical testing	The p.S334N variant (also known as c.1001G>A), located in coding exon 6 of the LMNA gene, results from a G to A substitution at nucleotide position 1001. The serine at codon 334 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in several individuals in cardiomyopathy and/or arrhythmia testing cohorts; however, clinical details were limited (van Spaendonck-Zwarts KY et al. Eur J Heart Fail, 2013 Jun;15:628-36; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Park J et al. Genet Med, 2020 Jan;22:102-111). This amino acid position is not well conserved in available vertebrate species, and asparagine is the reference amino acid in other 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.
Fulgent Genetics, Fulgent Genetics	RCV002478412	SCV002786047	uncertain significance	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2	2021-09-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726496	SCV003814697	uncertain significance	not provided	2019-12-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000148605	SCV004816976	uncertain significance	Primary dilated cardiomyopathy	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 334 of the lamin A/C protein. Computational prediction 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 at least 2 individuals affected with dilated cardiomyopathy (PMID: 23349452, 30847666, 32880476). It has also been reported in individuals affected with unspecified cardiomyopathy and aborted sudden cardiac death (PMID: 30847666). This variant has been identified in 6/281674 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.
CSER _CC_NCGL, University of Washington	RCV000148605	SCV000190320	uncertain significance	Primary dilated cardiomyopathy	2014-06-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000726496	SCV001741392	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000726496	SCV001925650	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000726496	SCV001929788	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000726496	SCV001957735	uncertain significance	not provided		no assertion criteria provided	clinical testing