Submissions for variant NM_170707.4(LMNA):c.1873A>T (p.Ser625Cys)

dbSNP: rs398124550

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691653	SCV000819439	uncertain significance	Charcot-Marie-Tooth disease type 2	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 625 of the LMNA protein (p.Ser625Cys). This variant is present in population databases (rs398124550, gnomAD 0.01%). 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: 570722). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	RCV001183076	SCV001348731	uncertain significance	Cardiomyopathy	2023-06-29	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 625 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An experimental study has suggested that the mutant protein assembles normally at the nuclear periphery but is associated with a compromise in cell cycle regulation (Thanumalayan et al., 2015). Clinical relevance of this observation is not known. This variant has been reported in an individual affected with dilated cardiomyopathy (Thanumalayan et al, 2015). This variant has been identified in 3/248596 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.
All of Us Research Program, National Institutes of Health	RCV003999563	SCV004833679	uncertain significance	Primary dilated cardiomyopathy	2023-07-10	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces serine with cysteine at codon 625 of the lamin A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental study has suggested that the mutant protein assembles normally at the nuclear periphery but is associated with a compromise in cell cycle regulation (Thanumalayan et al., 2015). Clinical relevance of this observation is not known. This variant has been reported in an Indian individual affected with dilated cardiomyopathy (Thanumalayan et al., 2015). This variant has been identified in 3/243748 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.