Submissions for variant NM_170707.4(LMNA):c.736C>T (p.Gln246Ter)

dbSNP: rs267607587

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057448	SCV000234680	pathogenic	not provided	2013-01-14	criteria provided, single submitter	clinical testing	p.Q246Stop (CAG>TAG): c.736 C>T in exon 4 of the LMNA gene (NM_170707.2). The Gln246Stop mutation in the LMNA gene has been reported in one individual with cardiomyopathy and atrioventricular block, and was absent from 392 control alleles in this study (Pasotti M et al., 2008). Gln246Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Numerous other nonsense mutations in the LMNA gene have been reported in association with cardiomyopathy. Therefore, the presence of this mutation indicates an increased risk to develop DCM. However, other genetic and environmental factors influence disease expression and severity, and some mutation carriers may never become symptomatic. The variant is found in DCM panel(s).
Invitae	RCV001854177	SCV002232091	pathogenic	Charcot-Marie-Tooth disease type 2	2020-12-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 29104234). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66927). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln246*) 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).
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057448	SCV000088562	not provided	not provided		no assertion provided	not provided
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000057448	SCV000280184	likely pathogenic	not provided	2012-12-01	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LMNA p.Gln246Stop Based on the data reviewed below, we consider this likely disease causing. The variant has been seen in at least one case of familial DCM with a laminopathy. There is no segregation data available. Pasotti et al (2008) reported the variant in one individual from their Italian cohort of 27 families with LMNA variants. That individual had dilated cardiomyopathy and AV block onset after 40 years old. This is a nonsense variant, which means the nucleotide substitution creates a premature stop codon. The variant is expected to results in no protein product due to nonsense-mediated mRNA decay and/or a truncated protein product. While this specific nonsense variant has only been seen in one other case, there is sufficient data supporting nonsense variants in LMNA in general as disease-causing. There are at least 11 different nonsense variants reported in LMNA associated with the various laminopathy phenotypes, including primarily dilated cardiomyopathy, conduction system disease, or muscular dystrophy (LGMD, EDMD) (Cowan J et al 2011, Dittmer et al 2011, http://www.dmd.nl/lmna_seqvar.html). Many frameshift variants have also been reported. We have seen another LMNA nonsense variant in a family with a familial cardiomyopathy consistent with the typical laminopathy phenotype. I reviewed the data on several other reported LMNA nonsense variants, which support this class of variants as disease causing. For example, Geiger et al (2007) report a nonsense variant (R321X) in a family with DCM and sudden death; three affected family members were genotyped and they all had the variant. mRNA and protein studies on patient skin fibroblasts and LV myocardium were consistent with mRNA mediated nonsense decay. In total this specific variant has not been seen in ~7143 published controls and individuals from publicly available population datasets. There are no nonsense or frameshift variants listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of January 27th, 2013). No nonsense variants were identified in 47 healthy elderly individuals studied by Halaschek-Wiener et al (2009). Familion told me that they have not seen any nonsense or frameshift variants in LMNA in their 400 controls. The variant is listed in dbSNP (rs267607587) but only in reference to the publications by Pasotti et al. The only nonsense variants in LMNA listed in dbSNP are from a clinical source (i.e. disease-causing variants) (as of January 27th, 2013). Similarly, there are no nonsense variants listed in the 1000 genomes browser as being observed in the 1000 genomes samples. This specific variant was not observed in the following published control samples: Pasotti et al (2008) did not observe this specific variant in 196 presumed healthy control individuals.