Submissions for variant NM_170707.4(LMNA):c.467G>A (p.Arg156His)

gnomAD frequency: 0.00004  dbSNP: rs764475194

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001526029	SCV001736292	uncertain significance	Cardiomyopathy	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 156 of the LMNA protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with atrial fibrillation (PMID: 35449878) and in one individual affected with familial partial lipodystrophy (PMID: 30287275). This variant has been identified in 1/243558 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	RCV001873686	SCV002127090	uncertain significance	Charcot-Marie-Tooth disease type 2	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 156 of the LMNA protein (p.Arg156His). 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: 1172290). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002224087	SCV002502350	uncertain significance	not provided	2021-09-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002334576	SCV002638173	uncertain significance	Cardiovascular phenotype	2021-06-18	criteria provided, single submitter	clinical testing	The p.R156H variant (also known as c.467G>A), located in coding exon 2 of the LMNA gene, results from a G to A substitution at nucleotide position 467. The arginine at codon 156 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a laminopathy cohort in an individual with familial partial lipodystrophy; however, clinical details were limited (Kwapich M et al. Diabetes Metab, 2019 09;45:382-389). This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002488345	SCV002790721	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	2022-02-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331176	SCV004037653	uncertain significance	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.467G>A (p.Arg156His) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of 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 4.1e-06 in 243558 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.467G>A has been reported in the literature in individuals affected with Familial Partial Lipodystrophy (Kwapich_2019) and Atrial Fibrillation (Pessente_2022). 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. The following publications have been ascertained in the context of this evaluation (PMID: 30287275, 35449878). Five ClinVar submitters have assessed the variant since 2014, and all five submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004008887	SCV004836014	uncertain significance	Primary dilated cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 156 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individual affected with familial partial lipodystrophy (PMID: 30287275). This variant has been identified in 1/243558 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.