Submissions for variant NM_170707.4(LMNA):c.1786G>A (p.Asp596Asn)

gnomAD frequency: 0.00001  dbSNP: rs769561386

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000503392	SCV000595638	pathogenic	Muscular dystrophy	2013-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV000653834	SCV000775724	likely pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 596 of the LMNA protein (p.Asp596Asn). This variant is present in population databases (rs769561386, gnomAD 0.005%). This missense change has been observed in individuals with Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 18035816, 21520333). ClinVar contains an entry for this variant (Variation ID: 435774). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Athena Diagnostics Inc	RCV000992277	SCV001144439	uncertain significance	not provided	2018-09-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001526033	SCV001736296	uncertain significance	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 596 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies using fibroblasts derived from heterozygous carrier individuals for this variant have shown this variant causes abnormal localization of chromosome 13 within the nuclei, suggesting impaired interaction with chromatin (PMID: 21179469, 21818408). This variant has been reported in an individual affected with limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 18035816) and in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 21520333). This variant has been identified in 6/277018 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	RCV000992277	SCV001981942	uncertain significance	not provided	2021-09-14	criteria provided, single submitter	clinical testing	Reported in one individual with limb girdle muscular dystrophy who presented with DCM and heart failure (Correa and Gmez, 2007); Published functional studies using fibroblast cell lines derived from a patient harboring the D596N variant found that while chromosome 13 was maintained at the nuclear periphery, there was gross mislocalization of this chromosome, suggesting that D596N impacts the nuclear lamina's ability to interact with chromatin (Mewborn et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21818408, 21970986, 10939567, 24481844, 27507988, 27200088, 29907918, 21520333, 21179469, 18035816)