Submissions for variant NM_170707.4(LMNA):c.952G>A (p.Ala318Thr)

gnomAD frequency: 0.00001  dbSNP: rs267607574

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852590	SCV000995292	likely benign	Primary dilated cardiomyopathy	2019-05-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182567	SCV001348062	uncertain significance	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 318 of the LMNA protein. 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). A functional study has shown that this variant does not alter protein localization or nuclear envelope morphology (PMID: 20160190). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 18585512, 20160190, 30012837); this individual also carried a pathogenic truncation variant in the TTN gene. The affected individual and affected parent both carried the TTN truncation variant, but LMNA p.Ala318Thr did not segregate with disease in the family (PMID: 30012837). This variant has also been reported in individuals affected with arrhythmia (PMID: 30847666). This variant has been identified in 5/280050 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.
Invitae	RCV001303998	SCV001493265	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 318 of the LMNA protein (p.Ala318Thr). This variant is present in population databases (rs267607574, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy or arrhythmia (PMID: 30012837, 30847666). ClinVar contains an entry for this variant (Variation ID: 66961). 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 have shown that this missense change does not substantially affect LMNA function (PMID: 20160190, 34862408). 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.
GeneDx	RCV000057491	SCV001772187	uncertain significance	not provided	2020-09-14	criteria provided, single submitter	clinical testing	Reported in one patient with DCM; however, it did not co-segregate with disease in this family (Parks et al., 2008); Reported in ClinVar (ClinVar Variant ID# 66961; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 20160190, 30012837, 18585512, 21639948, 24846508, 22224630)
Ambry Genetics	RCV002371900	SCV002686781	uncertain significance	Cardiovascular phenotype	2018-11-07	criteria provided, single submitter	clinical testing	The p.A318T variant (also known as c.952G>A), located in coding exon 6 of the LMNA gene, results from a G to A substitution at nucleotide position 952. The alanine at codon 318 is replaced by threonine, an amino acid with similar properties. This variant was reported in one individual with familial dilated cardiomyopathy (DCM), but was not detected in his affected mother who had a later age of onset (Parks SB et al. Am. Heart J., 2008 Jul;156:161-9). Subsequent exome analysis detected additional cardiac variants that were present in both affected family members; at that time the possibility of multigenic effects on age of onset were suggested (Cowan JR et al. Circ Genom Precis Med, 2018 Jul;11:e002038). Limited in vitro analysis did not demonstrate significant differences in protein localization pattern or nuclear morphology (Cowan J et al. Circ Cardiovasc Genet, 2010 Feb;3:6-14). This amino acid position is well 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.
Revvity Omics, Revvity	RCV000057491	SCV003816987	uncertain significance	not provided	2020-09-08	criteria provided, single submitter	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057491	SCV000088605	not provided	not provided		no assertion provided	not provided
University of Washington Center for Mendelian Genomics, University of Washington	RCV000852590	SCV001434745	uncertain significance	Primary dilated cardiomyopathy		no assertion criteria provided	research