ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.521C>A (p.Ala174Glu)

dbSNP: rs762153472
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001191015 SCV001358685 uncertain significance Cardiomyopathy 2020-12-09 criteria provided, single submitter clinical testing This missense variant replaces alanine with glutamic acid at codon 174 of the lamin A/C proteins. 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251360 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 RCV001863029 SCV002312876 uncertain significance Charcot-Marie-Tooth disease type 2 2023-07-07 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 174 of the LMNA protein (p.Ala174Glu). This variant is present in population databases (rs762153472, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 927619). 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. 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.
Ambry Genetics RCV002348638 SCV002646724 uncertain significance Cardiovascular phenotype 2022-01-06 criteria provided, single submitter clinical testing The p.A174E variant (also known as c.521C>A), located in coding exon 3 of the LMNA gene, results from a C to A substitution at nucleotide position 521. The alanine at codon 174 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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