ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.356G>C (p.Arg119Pro) (rs397517902)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000041347 SCV000614028 uncertain significance not specified 2016-09-06 criteria provided, single submitter clinical testing
GeneDx RCV000767136 SCV000234735 uncertain significance not provided 2017-09-14 criteria provided, single submitter clinical testing The R119P variant of uncertain significance was identified in the LMNA gene. The R119P variant was reported in a 44-year-old female with a clinical history of DCM with ventricular tachycardia and a family history of arrhythmia and sudden death (Pugh et al., 2014). Additionally, this variant has been reported in a patient referred for DCM genetic testing (Walsh et al., 2017). However, to our knowledge no studies have been performed to determine the functional effect of this variant. The R119P variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. Nevertheless, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R119P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Laboratory for Molecular Medicine,Partners HealthCare 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
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.

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