Submissions for variant NM_170707.4(LMNA):c.1756G>A (p.Val586Met)

gnomAD frequency: 0.00003  dbSNP: rs758048062

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000686535	SCV000814056	uncertain significance	Charcot-Marie-Tooth disease type 2	2022-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 586 of the LMNA protein (p.Val586Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 487635). 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.
Fulgent Genetics, Fulgent Genetics	RCV002476258	SCV000896163	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	2022-04-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251364	SCV001426936	uncertain significance	not specified	2020-07-20	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.1756G>A (p.Val586Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 243662 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1756G>A has been reported in the literature in at least one patient from the UMD laminopathy database (e.g. Florwick_2017). The variant was also detected in an individual who had exome sequencing (Park_2019). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509066	SCV001715577	uncertain significance	not provided	2019-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002404581	SCV002711682	uncertain significance	Cardiovascular phenotype	2019-12-04	criteria provided, single submitter	clinical testing	The p.V586M variant (also known as c.1756G>A), located in coding exon 11 of the LMNA gene, results from a G to A substitution at nucleotide position 1756. The valine at codon 586 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in an exome cohort, but clinical details were limited (Florwick A et al. Front Genet. 2017;8:79). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001509066	SCV003814731	uncertain significance	not provided	2021-03-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001216	SCV004832950	uncertain significance	Primary dilated cardiomyopathy	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 586 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 with possible laminopathy (PMID: 28663758). This variant has been identified in 3/243662 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.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656219	SCV000678413	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome