ClinVar Genomic variation as it relates to human health

The Arg225X variant in LMNA leads to a premature stop at codon 225, which is pre dicted to lead to a truncated or absent protein. This variant has been reported in 4 individuals with variable clinical features that included DCM, conduction s ystem disease, and musculoskeletal abnormalities (Jakobs 2001, Van Tintelen 2007 , Saga 2009, Carboni 2010). These presentations are typical manifestations of pa thogenic LMNA variants. In addition, this variant segregated with disease in at least 7 affected family members and was absent from at least 600 control chromo somes (Jakobs 2001, Van Tintelen 2007, Saga 2009, Carboni 2010). In summary, the Arg225X variant meets our criteria for pathogenicity based on the severity of t he change, segregation in affected individuals, and absence from controls.

This sequence change creates a premature translational stop signal (p.Arg225*) in the LMNA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with LMNA-related conditions (PMID: 11561226, 22806367, 23362510). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48074). For these reasons, this variant has been classified as Pathogenic.

The p.R225* pathogenic mutation (also known as c.673C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide position 673. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in numerous individuals with LMNA-related phenotypes, including dilated cardiomyopathy, cardiac conduction disease, and musculoskeletal abnormalities (van Tintelen JP et al. Am. Heart J. 2007;154:1130-9; Saga A et al. Tohoku J. Exp. Med. 2009;218:309-16; Laksman Z et al. Clin. Genet. 2014;86:580-4; Mellor G et al. Circ Cardiovasc Genet. 2017;10(3): e001686; Nishiuchi S et al. Circ Cardiovasc Genet. 2017;10(6):e001603; Walsh R et al. Genet. Med. 2017;19:192-203). Moreover, this alteration segregated with disease in multiple large families (Jakobs PM et al. J. Card. Fail. 2001;7:249-56; Carboni N et al. Muscle Nerve. 2012;46:187-92; Siu CW et al. Aging (Albany NY). 2012;4:803-822; Arimura T et al. Cardiovasc. Res. 2013;99:382-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as this variant results in accelerated nuclear senescence and apoptosis of cardiomyocytes (Siu et al., 2012); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 48074; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 11561226, 18035086, 25525159, 19638735, 23631840, 24237251, 27054045, 23362510, 24503780, 19882644, 27532257, 28573431, 28600387, 31395619, 31668660, 31427369, 28754655, 31309180, 30934932, 30078822, 32793522, 31383942, 32160020, 31402444)

PVS1, PS4, PM2, PP1

PVS1, PS3, PS4, PM2