Submissions for variant NM_170707.4(LMNA):c.1003del (p.Arg335fs)

dbSNP: rs1553265660

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552796	SCV000657786	pathogenic	Charcot-Marie-Tooth disease type 2	2023-05-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 476818). 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 creates a premature translational stop signal (p.Arg335Glyfs*145) 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).
Illumina Laboratory Services, Illumina	RCV000778941	SCV000915359	uncertain significance	LMNA-related disorder	2018-11-14	criteria provided, single submitter	clinical testing	The LMNA c.1003delC (p.Arg335GlyfsTer145) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for LMNA-related disorders.
Ambry Genetics	RCV002404566	SCV002704095	pathogenic	Cardiovascular phenotype	2023-06-22	criteria provided, single submitter	clinical testing	The c.1003delC pathogenic mutation, located in coding exon 6 of the LMNA gene, results from a deletion of one nucleotide at nucleotide position 1003, causing a translational frameshift with a predicted alternate stop codon (p.R335Gfs*145). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.