Submissions for variant NM_170707.4(LMNA):c.985C>T (p.Arg329Cys)

dbSNP: rs775159300

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000657946	SCV000709340	uncertain significance	not provided	2017-06-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000657946	SCV000779716	uncertain significance	not provided	2018-05-10	criteria provided, single submitter	clinical testing	The R329C variant has been reported previously in an individual with long QT syndrome; however, this individual also had a pathogenic variant in the SCN5A gene identified (Piccoli et al., 2017). The R329C variant is observed in 1/33568 (0.003%) alleles from individuals of Latino background (Lek et al., 2016). The R329C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The R329C variant is located within the alpha-helical rod domain (Bonne et al., 2000). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000692895	SCV000820743	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-09-10	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 502552). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 329 of the LMNA protein (p.Arg329Cys).
Color Diagnostics, LLC DBA Color Health	RCV001178642	SCV001343145	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 329 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with long QT syndrome, who also carried a pathogenic variant in the SCN5A gene (PMID: 28118183). This variant has been identified in 1/249934 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.
Ambry Genetics	RCV003160061	SCV003864676	uncertain significance	Cardiovascular phenotype	2022-12-14	criteria provided, single submitter	clinical testing	The p.R329C variant (also known as c.985C>T), located in coding exon 6 of the LMNA gene, results from a C to T substitution at nucleotide position 985. The arginine at codon 329 is replaced by cysteine, an amino acid with highly dissimilar properties. 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.