Submissions for variant NM_170707.4(LMNA):c.1862C>T (p.Thr621Met)

gnomAD frequency: 0.00008  dbSNP: rs765594825

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000687429	SCV000814994	likely benign	Charcot-Marie-Tooth disease type 2	2023-12-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001191647	SCV001359542	uncertain significance	Cardiomyopathy	2023-09-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 621 of the lamin A 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 arrhythmogenic right ventricular cardiomyopathy and sudden cardiac death (PMID: 26383259), in an individual affected with cardiomyopathy (PMID: 31383942), and in an individual affected with conduction defect (PMID: 31383942). This variant has been identified in 7/279750 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193913	SCV001363086	uncertain significance	not specified	2019-12-10	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.1862C>T (p.Thr621Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1862C>T has been reported in the literature in an individual affected with sudden cardiac death (Hertz_2016). Thi report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001572302	SCV001796916	uncertain significance	not provided	2022-08-30	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26383259, 10939567)
Ambry Genetics	RCV002406543	SCV002722223	uncertain significance	Cardiovascular phenotype	2022-12-01	criteria provided, single submitter	clinical testing	The p.T621M variant (also known as c.1862C>T), located in coding exon 11 of the LMNA gene, results from a C to T substitution at nucleotide position 1862. The threonine at codon 621 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a sudden unexplained death cohort and a whole exome sequencing cohort (Hertz CL et al. Int J Legal Med, 2016 Jan;130:91-102; Park J et al. Genet Med, 2020 Jan;22:102-111). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Athena Diagnostics Inc	RCV001572302	SCV002771303	uncertain significance	not provided	2021-06-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002493155	SCV002797705	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	2022-05-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001572302	SCV003814707	uncertain significance	not provided	2019-01-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004266	SCV004833106	uncertain significance	Primary dilated cardiomyopathy	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 621 of the lamin A 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 arrhythmogenic right ventricular cardiomyopathy and sudden cardiac death (PMID: 26383259), in an individual affected with cardiomyopathy (PMID: 31383942), and in an individual affected with conduction defect (PMID: 31383942). This variant has been identified in 7/279750 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.