Submissions for variant NM_170707.4(LMNA):c.768G>A (p.Val256=)

gnomAD frequency: 0.00001  dbSNP: rs794728593

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182364	SCV000234683	pathogenic	not provided	2021-05-04	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #200941; Landrum et al., 2016); Published functional studies demonstrate premature splicing of exon 4 which deleted the terminal 45 base pairs and resulted in the loss of 15 aa in the rod domain of LMNA; In silico analyses, including splice predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 28679633)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219229	SCV000271392	pathogenic	Primary dilated cardiomyopathy	2017-11-14	criteria provided, single submitter	clinical testing	The p.Val256Val variant in LMNA has been identified in 1 family with DCM and sud den death and segregated with disease in >35 affected relatives (Ito 2017). Sequ encing of RNA from individuals carrying the variant showed that this variant cau ses premature splicing of exon 4, resulting in a terminal deletion of 45 bps and loss of the last 15 amino acids of the exon (Ito 2017). This variant has not be en identified in large population studies. In summary, this variant meets criter ia to be classified as pathogenic for DCM in an autosomal dominant manner based upon its functional impact and segregation in affected individuals. ACMG/AMP Cri teria applied: PS3; PP1_Strong; PM2; PP3
Invitae	RCV000806148	SCV000946130	pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change affects codon 256 of the LMNA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LMNA protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 15 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with dilated cardiomyopathy with conduction disease (PMID: 28679633). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200941). Studies have shown that this variant results in the activation of a cryptic splice site in exon 4 (PMID: 28679633). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199263	SCV001370326	pathogenic	Dilated cardiomyopathy 1A	2019-05-16	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2.
Ambry Genetics	RCV002399655	SCV002673635	pathogenic	Cardiovascular phenotype	2019-02-14	criteria provided, single submitter	clinical testing	The c.768G>A pathogenic mutation (also known as p.V256V), located in coding exon 4, results from a G to A substitution at nucleotide position 768 of the LMNA gene. This nucleotide substitution does not change the amino acid at codon 256. This alteration has been reported in a multi-generation family with dilated cardiomyopathy (DCM) and conduction system disease, where strong disease segregation was identified (Lynch HT et al. JAMA, 1973 Sep;225:1465-70; Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 Jul;114:7689-7694). This mutation was also reported in affected individuals from an additional family with a history of DCM and sudden cardiac death (Duong et al., J Biol Methods, 2017 Sept;4(3):e78). In addition, an aberrant transcript that lacks the last 45bp of exon 4 was identified in patients from the original family, as well as in mini-gene assays (Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 Jul;114:7689-7694). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.