Submissions for variant NM_170707.4(LMNA):c.1517A>C (p.His506Pro)

gnomAD frequency: 0.00003  dbSNP: rs878855233

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000227241	SCV000291550	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 506 of the LMNA protein (p.His506Pro). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27813223). ClinVar contains an entry for this variant (Variation ID: 242003). 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 with a positive predictive value of 95%. 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.
GeneDx	RCV000235371	SCV000292723	uncertain significance	not provided	2015-06-04	criteria provided, single submitter	clinical testing	The H506P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H506P variant was not observed in approximately 6500 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 H506P 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 most mammals, however Proline is the wild type residue at this position in platypus and Alanine is present at this position in alpaca. Missense mutations in this residue (H506D) and nearby residues (W498R, W498C, L512P) have been reported in the Human Gene Mutation Database in association with metabolic laminopathy, muscular dystrophy and myopathy (Stenson et al., 2014), 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.
Center for Human Genetics, University of Leuven	RCV000498163	SCV000579568	uncertain significance	Hypertrophic cardiomyopathy	2017-04-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777786	SCV000913764	uncertain significance	Cardiomyopathy	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 506 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). Experimental studies have shown that this variant impacts the interaction with Ankrd2 (PMID: 28531892) and Samp1 (PMID: 30326651), leading to altered subcellular localization of these proteins. This variant has been reported in an individual affected with dilated cardiomyopathy (DOI:10.1093/europace/18.suppl_1.i167a), in an individual affected with hypertrophic cardiomyopathy (PMID: 29255176), in an individual affected with Emery-Dreifuss Muscular Dystrophy (PMID: 28531892), and in an individual affected with laminopathy in the absence of neuromuscular involvement (PMID: 31744510). This variant has been identified in 9/280138 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.
Illumina Laboratory Services, Illumina	RCV001098894	SCV001255291	uncertain significance	Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules	2019-06-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001098895	SCV001255292	uncertain significance	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2019-06-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001098896	SCV001255293	uncertain significance	Dilated cardiomyopathy 1A	2019-06-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001100712	SCV001257243	uncertain significance	Mandibuloacral dysplasia with type A lipodystrophy	2019-06-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001100713	SCV001257245	uncertain significance	Hutchinson-Gilford syndrome	2019-06-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001100714	SCV001257246	uncertain significance	Charcot-Marie-Tooth disease type 2B1	2019-06-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001100715	SCV001257247	uncertain significance	Lethal tight skin contracture syndrome	2019-06-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001100716	SCV001257248	uncertain significance	Congenital muscular dystrophy due to LMNA mutation	2019-06-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001100717	SCV001257249	uncertain significance	Emery-Dreifuss muscular dystrophy	2019-06-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001100718	SCV001257250	uncertain significance	Familial partial lipodystrophy, Dunnigan type	2019-06-06	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298550	SCV002599026	uncertain significance	not specified	2022-09-12	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.1517A>C (p.His506Pro) results in a non-conservative amino acid change located in the Lamin tail domain (IPR001322) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 248754 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1517A>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy (example, Jansweijer_2017, Hoorntje_2017, Verdonschot_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function reporting an altered interaction between prelamin A and Ankrd2 resulting in mislocalization of Ankrd2 in the nucleus (example, Angori_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002392721	SCV002708580	uncertain significance	Cardiovascular phenotype	2021-07-16	criteria provided, single submitter	clinical testing	The p.H506P variant (also known as c.1517A>C), located in coding exon 9 of the LMNA gene, results from an A to C substitution at nucleotide position 1517. The histidine at codon 506 is replaced by proline, an amino acid with similar properties. This alteration has been reported in one participant from a dilated cardiomyopathy (DCM) cohort (Jansweijer JA et al. Eur. J. Heart Fail., 2017 04;19:512-521), and, although details were limited, in an individual with Emery-Dreifuss muscular dystrophy 2 (EDMD2) (Angori S et al. Cell. Physiol. Biochem., 2017 May;42:169-184). Functional studies have suggested that p.H506P alters localization of Ankrd2 and Samp1 proteins in muscle cells, while a study of fibroblasts and myoblasts derived from an EDMD2 patient heterozygous for p.H506P revealed increased TGF-beta2 serum levels; however, the physiological relevance of these results is unclear (Angori S et al. Cell. Physiol. Biochem., 2017 May;42:169-184; Mattioli E et al. Cells, 2018 Oct;7; Bernasconi P et al. Nucleus, 2018 Jan;9:292-304). This amino acid position is well conserved in available vertebrate species; however, proline is the reference amino acid in other 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	RCV002500822	SCV002814242	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	2022-02-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000235371	SCV004124992	uncertain significance	not provided	2023-04-01	criteria provided, single submitter	clinical testing	LMNA: PM1, PM2:Supporting, PS4:Supporting