Submissions for variant NM_170707.4(LMNA):c.161C>T (p.Thr54Met)

dbSNP: rs879253992

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000237062	SCV000293089	uncertain significance	not provided	2015-08-26	criteria provided, single submitter	clinical testing	The T54M variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T54M 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. This substitution occurs at a position that is conserved in mammals. In addition, multiple missense variants in nearby residues (L52V, L52P, E53V, E53G, A57P, L59R, R60G, R62G) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), further supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000653891	SCV000775781	uncertain significance	Charcot-Marie-Tooth disease type 2	2017-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 54 of the LMNA protein (p.Thr54Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LMNA-related disease. ClinVar contains an entry for this variant (Variation ID: 245899). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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	RCV001176604	SCV001340632	uncertain significance	Cardiomyopathy	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 54 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666); this individual also carried a different pathogenic missense variant in the LMNA gene. This variant has also been reported in an individual affected with hypertrophic cardiomyopathy and in an individual affected with arrhythmia (PMID: 30847666). This variant has been identified in 1/214730 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000237062	SCV002541088	uncertain significance	not provided	2021-04-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002479941	SCV002782002	uncertain significance	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2	2022-04-04	criteria provided, single submitter	clinical testing