Submissions for variant NM_170707.4(LMNA):c.632A>G (p.Tyr211Cys)

gnomAD frequency: 0.00001  dbSNP: rs987157491

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170452	SCV001333032	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175610	SCV001339264	uncertain significance	not specified	2020-03-23	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.632A>G (p.Tyr211Cys) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7e-06 in 143316 control chromosomes (gnomAD v3, genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.632A>G has been reported in the literature in and individual affected with Dilated Cardiomyopathy (DCM) (Tobita_2018). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001301048	SCV001490205	pathogenic	Charcot-Marie-Tooth disease type 2	2023-09-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 915590). 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. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with clinical features consistent with autosomal dominant arrhythmogenic cardiomyopathy and/or clinical features of LMNA-related conditions (PMID: 29386531, 32789579; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 211 of the LMNA protein (p.Tyr211Cys). This variant is present in population databases (no rsID available, gnomAD 0.007%).
Ambry Genetics	RCV002355132	SCV002654586	uncertain significance	Cardiovascular phenotype	2022-08-10	criteria provided, single submitter	clinical testing	The p.Y211C variant (also known as c.632A>G), located in coding exon 3 of the LMNA gene, results from an A to G substitution at nucleotide position 632. The tyrosine at codon 211 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a cardiomyopathy cohort and a sudden infant death cohort; however, clinical details were limited in both cases (Tobita T et al. Sci Rep, 2018 01;8:1998; Köffer J et al. Int J Legal Med, 2021 Jan;135:207-212). This amino acid position is well 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.
Revvity Omics, Revvity	RCV003132248	SCV003814676	uncertain significance	not provided	2019-05-30	criteria provided, single submitter	clinical testing