Submissions for variant NM_170707.4(LMNA):c.1748C>T (p.Ser583Leu)

gnomAD frequency: 0.00002  dbSNP: rs59601651

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057354	SCV000234710	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	Reported in the published literature in association with partial lipodystrophy, however, detailed clinical information was not provided in all cases (Semple et al., 2009; Verstraeten et al., 2006; Patni et al., 2019; Park et al., 2002; Savage et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17711925, 16357800, 16825282, 16705075, 19164855, 24623722, 18031308, 21639948, 20074070, 27841971, 29557732, 28663758, 32193531, 33356916, 33916827, 29431110, 31383942, 30418556, 15298354, 36397776, 10939567)
Ambry Genetics	RCV000618100	SCV000735752	uncertain significance	Cardiovascular phenotype	2017-03-01	criteria provided, single submitter	clinical testing	The p.S583L variant (also known as c.1748C>T), located in coding exon 11 of the LMNA gene, results from a C to T substitution at nucleotide position 1748. The serine at codon 583 is replaced by leucine, an amino acid with dissimilar properties, and is located in the C-terminal tail. This alteration has been reported to segregate with disease in individuals from three families with familial partial lipodystrophy; however, more severe phenotypes were seen in individuals who were compound heterozygotes with p.S583L and an additional LMNA alteration (Savage DB et al. Diabetologia, 2004 Apr;47:753-6). 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.
Invitae	RCV000653858	SCV000775748	pathogenic	Charcot-Marie-Tooth disease type 2	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 583 of the LMNA protein (p.Ser583Leu). This variant is present in population databases (rs59601651, gnomAD 0.005%). This missense change has been observed in individuals with autosomal dominant lipodystrophy (PMID: 15298354). It has also been observed to segregate with disease in related individuals. It has also been observed in individuals with no known history of LMNA-related conditions, which indicates that penetrance of this variant may be incomplete. ClinVar contains an entry for this variant (Variation ID: 66864). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 24623722). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001182287	SCV001347687	uncertain significance	Cardiomyopathy	2023-08-10	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 583 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). A functional study has shown that this variant does not significantly affect protein-protein interactions (PMID: 24623722). This variant has been reported in multiple families affected with familial partial lipodystrophy (PMID: 15298354, 30418556, 32193531, 36397776). This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/242708 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.
Fulgent Genetics, Fulgent Genetics	RCV002504960	SCV002816817	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	2021-10-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000057354	SCV003814692	uncertain significance	not provided	2020-02-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333022	SCV004040850	likely pathogenic	Familial partial lipodystrophy, Dunnigan type	2023-07-24	criteria provided, single submitter	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057354	SCV000088467	not provided	not provided		no assertion provided	not provided