Submissions for variant NM_170707.4(LMNA):c.1871G>A (p.Arg624His)

gnomAD frequency: 0.00001  dbSNP: rs13768

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000057367	SCV000704757	uncertain significance	not provided	2016-12-29	criteria provided, single submitter	clinical testing
Invitae	RCV001046717	SCV001210631	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-08-27	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs13768, gnomAD 0.007%). This missense change has been observed in individual(s) with Emery-Dreifuss muscular dystrophy (PMID: 11503164). ClinVar contains an entry for this variant (Variation ID: 66870). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 24623722). 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. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 624 of the LMNA protein (p.Arg624His).
Color Diagnostics, LLC DBA Color Health	RCV001182170	SCV001347525	uncertain significance	Cardiomyopathy	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 624 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Emery-Dreifuss muscular dystrophy who also carried a different pathogenic missense variant in the same gene (PMID: 11503164, 20848652). This variant has been identified in 6/248278 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.
GeneDx	RCV000057367	SCV001985352	uncertain significance	not provided	2019-04-19	criteria provided, single submitter	clinical testing	Identified in a patient with Emery-Dreifuss muscular dystrophy type 2 in the published literature, though it was also observed in conjunction with another LMNA variant and was also observed in his clinically unaffected father (Brown et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar Variant ID# 66870; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 11973618, 11503164, 29764566)
Ambry Genetics	RCV004018990	SCV003745281	uncertain significance	Cardiovascular phenotype	2021-09-24	criteria provided, single submitter	clinical testing	The c.1871G>A (p.R624H) alteration is located in exon 11 (coding exon 11) of the LMNA gene. This alteration results from a G to A substitution at nucleotide position 1871, causing the arginine (R) at amino acid position 624 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
New York Genome Center	RCV003227630	SCV003925382	uncertain significance	Dilated cardiomyopathy 1A	2022-03-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996509	SCV004825442	uncertain significance	Primary dilated cardiomyopathy	2023-04-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 624 of the lamin A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygosity with p.Glu358Lys in an individual severely affected with Emery-Dreifuss muscular dystrophy, and her heterozygous father was clinically unaffected (PMID: 11503164). A later study has reported three other patients heterozygous for p.Glu358Lys who were severely affected with Emery-Dreifuss muscular dystrophy, making the role of p.Arg624His unclear (PMID: 20848652). This variant has been identified in 6/248278 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.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057367	SCV000088480	not provided	not provided		no assertion provided	not provided