Submissions for variant NM_170707.4(LMNA):c.1445G>T (p.Arg482Leu) (rs11575937)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000015580	SCV000915360	uncertain significance	Familial partial lipodystrophy 2	2019-01-09	criteria provided, single submitter	clinical testing	The LMNA c.1445G>T (p.Arg482Leu) variant has been identified in one family with partial lipodystrophy (Shackleton et al. 2000). This variant was found in a heterozygous state in the proband, affected mother, and affected maternal uncle and was not found in the sibling (age 10 years, whose disease state was equivocal at the time of ascertainment), unaffected father, or unaffected maternal grandmother. The p.Arg482Leu variant was absent from 100 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. The Arg482 residue is highly conserved and is a known variant hotspot. Functional studies showed that the p.Arg482Leu variant resulted in the formation of abnormal nuclear aggregates of lamin and failure of lamin to interact with emerin (Capanni et al. 2003; Hubner et al. 2006). Meaburn et al. (2007) showed that the variant resulted in a significant increase in percentage of cells undergoing apoptosis and in the repositioning of chromosomes 13 and X away from the nuclear periphery. Perepelina et al. (2018) demonstrated decreased Notch signaling for the p.Arg482Leu variant compared to controls and decreased adipogenic differentiation in response to Notch activation. Based on the collective evidence, the p.Arg482Leu variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial partial lipodystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina	RCV001097055	SCV001253306	uncertain significance	Mandibuloacral dysplasia with type A lipodystrophy	2017-04-27	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 Clinical Services Laboratory,Illumina	RCV001097056	SCV001253307	uncertain significance	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2017-04-27	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 Clinical Services Laboratory,Illumina	RCV001098782	SCV001255170	uncertain significance	Dilated cardiomyopathy 1A	2017-04-27	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 Clinical Services Laboratory,Illumina	RCV001098783	SCV001255171	uncertain significance	Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules	2017-04-27	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 Clinical Services Laboratory,Illumina	RCV001098784	SCV001255172	uncertain significance	Hutchinson-Gilford syndrome	2017-04-27	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 Clinical Services Laboratory,Illumina	RCV001098785	SCV001255173	uncertain significance	Charcot-Marie-Tooth disease type 2B1	2017-04-27	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 Clinical Services Laboratory,Illumina	RCV001098786	SCV001255174	uncertain significance	Emery-Dreifuss muscular dystrophy	2017-04-27	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 Clinical Services Laboratory,Illumina	RCV001098787	SCV001255175	uncertain significance	Lethal tight skin contracture syndrome	2017-04-27	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 Clinical Services Laboratory,Illumina	RCV001098788	SCV001255176	uncertain significance	Congenital muscular dystrophy, LMNA-related	2017-04-27	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.
OMIM	RCV000015580	SCV000035845	pathogenic	Familial partial lipodystrophy 2	2000-02-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057300	SCV000088413	not provided	not provided		no assertion provided	not provided