Submissions for variant NM_170707.4(LMNA):c.20G>A (p.Arg7Gln)

gnomAD frequency: 0.00001  dbSNP: rs751916168

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000476932	SCV000548854	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-03-20	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 408991). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is present in population databases (rs751916168, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 7 of the LMNA protein (p.Arg7Gln). 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	RCV001181379	SCV001346513	uncertain significance	Cardiomyopathy	2019-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 7 of the LMNA protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/175212 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.
Phosphorus, Inc.	RCV001823729	SCV002073428	uncertain significance	not specified	2022-01-17	criteria provided, single submitter	clinical testing	This missense variant results in a substitution of arginine with glutamine at codon 7 of the LMNA gene (transcript NM_170707.3). This variant has been reported in ClinVar (408991) NM_170707.4 (LMNA):c.20G>A (p.Arg7Gln) and occurred once in GnomAD with a total MAF of 0.0006% and highest MAF of 0.0037% in the Latin American population. This position is conserved. In silico functional algorithms agree, predicting it as benign (PolyPhen/REVEL) and tolerated (SIFT), but no functional studies were performed to confirm these predictions. The variant has not occurred in the literature associated with the disease. Two different missense changes nearby have been determined to be pathogenic (c.11C>G (p.Pro4Arg), c.29C>T (p.Thr10Ile)). In conclusion, the available evidence is insufficient to determine the pathogenicity of this variant. Therefore, it is classified as a Variant of Uncertain Significance.