Submissions for variant NM_170707.4(LMNA):c.760G>A (p.Asp254Asn)

dbSNP: rs1553265346

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521265	SCV000621129	uncertain significance	not provided	2017-09-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the LMNA gene. The D254N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D254N variant is not observed in large population cohorts (Lek et al., 2016). The D254N variant is a a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Color Diagnostics, LLC DBA Color Health	RCV001179089	SCV001343682	uncertain significance	Cardiomyopathy	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 254 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LMNA-related disorders in the literature. This variant has not been identified 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.
Invitae	RCV001313277	SCV001503765	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-01-19	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 254 of the LMNA protein (p.Asp254Asn).
Fulgent Genetics, Fulgent Genetics	RCV002481732	SCV002787328	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	2021-07-16	criteria provided, single submitter	clinical testing