Submissions for variant NM_170707.4(LMNA):c.1198G>A (p.Gly400Ser)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002344445	SCV002645223	uncertain significance	Cardiovascular phenotype	2020-05-15	criteria provided, single submitter	clinical testing	The p.G400S variant (also known as c.1198G>A), located in coding exon 7 of the LMNA gene, results from a G to A substitution at nucleotide position 1198. The glycine at codon 400 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and serine 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224629	SCV003920150	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	2021-03-30	criteria provided, single submitter	clinical testing	LMNA NM_005572.3 exon 7 p.Gly400Ser (c.1198G>A): This variant has not been reported in the literature and is not present in large control databases. This variant amino acid Serine (Ser) is present in >15 bird and reptile species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003776080	SCV004650730	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 400 of the LMNA protein (p.Gly400Ser). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 1746556). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LMNA protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.