Submissions for variant NM_170707.4(LMNA):c.356G>C (p.Arg119Pro)

dbSNP: rs397517902

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041347	SCV000065040	uncertain significance	not specified	2014-08-20	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000767136	SCV000234735	uncertain significance	not provided	2020-02-25	criteria provided, single submitter	clinical testing	Reported in association with dilated cardiomyopathy; however, additional clinical information was not provided (Pugh et al., 2014; Walsh et al., 2017); Reported in ClinVar by other clinical laboratories as a variant of uncertain significance (ClinVar Variant ID# 48064; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 27532257, 28679633)
Athena Diagnostics Inc	RCV000041347	SCV000614028	uncertain significance	not specified	2016-09-06	criteria provided, single submitter	clinical testing
Invitae	RCV003581568	SCV004292904	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 119 of the LMNA protein (p.Arg119Pro). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy and/or dilated cardiomyopathy (PMID: 24503780, 27532257, 36548481). ClinVar contains an entry for this variant (Variation ID: 48064). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (PMID: 28679633). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000767136	SCV000925143	likely pathogenic	not provided	2017-12-15	no assertion criteria provided	provider interpretation	We identified this variant in a patient with dilated cardiomyopathy and limb girdle muscular dystrophy. SCICD Classification: likely pathogenic variant based on absence in the general population, moderate case data, moderate segregation and position of variant. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"), however family members should be counseled about probabilistic nature of genetic testing. Additional case data or segregation could provide additional evidence towards pathogenicity. Gene-level evidence: LMNA: Pathogenic variants in LMNA cause clinically variable diseases, called the laminopathies. These include dilated cardiomyopathy (DCM), which is typically accompanied by conduction system disease and/or arrhythmias. Sudden cardiac death can occur before the onset of LV dilation, warranting early consideration of an ICD. Other laminopathies include Emery-Dreifuss muscular dystrophy, Hutchinson-Gilford progeria syndrome and lipodystrophies, among others. Region-level evidence: according to Amr et al 2016, this variant falls within the filament domain, a region that is greatly enriched for intolerance to variant in cases vs. controls (OR: 152). Case data (not including our patient): 3 · I contacted Gene Dx and they reported they have seen the variant in 2 probands (one who harbored additional variants) who had cardiomyopathy panels. LMM has seen it in 1 patient and it overlaps with that reported by Pugh 2014. · Cases in the literature: 1 (redudant with lab data_ ? Pugh 2014: reported in 44yo woman with clinical dx of DCM with VF and family history of arrhythmia and sudden death. Classified as likely pathogenic. No other disease causing variants reported. Segregation data: To our knowledge, clnical colleagues at a different institution have seen this variant in a family where it segregates in 4 affected family members (may overlap with cases reported by genetic testing laboratories. Our patient's affected brother was apparently tested and was positive. Functional data: None reported In silico data (missense variants only): Per various prediction models in varsome.com, the variant is disease causing/deleterious. Of note, the variant does alter the last amino acid at the exon/intron junction, which could possible affect splicing. Nearby pathogenic variants at this codon or neighboring codons: A different variant at the same position (c.354_355delGCinsAG; p.Arg119Gly) is listed as likely pathogenic in ClinVar by Blueprint. No summary evidence provided. Population data: Absent The variant is absent from the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is 33x whereas in exomes it is 60x.