Description
c.513+2T>G in intron 3 (2 nucleotides after coding exon 2) of the LMNA gene (NM_170707.2; chr1-156100566-T-G) SCICD Classification: likely pathogenic, due to likely loss of function and absence in general population databases. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"), if we are able to get one more affected family member with this variant (if it segregates in this patient). Gene-level evidence: 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: This variant is located within a region of LMNA in which the amount of variation in cases is significantly higher than the amount of variation in controls (Amr et al. 2016). Case data (not including our patient): none · ClinVar: not present. However, all splice variants in LMNA submitted to ClinVar by clinical labs are classified as either pathogenic or likely pathogenic. · Cases in the literature: none reported Segregation data: none reported. However, this variant segregates with cardiomyopathy and conduction system disease in 2 members of one family (this family). Functional data: none reported. Impact on splicing not corroborated with functional studies. Splice site data: Per the test report, "usingthe BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native canonical splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice donor site are typically deleterios in nature." This variant replaces a nucleotide at the position of a canonical splice site (+2). Conservation data: The thymine at position 513+2 is completely conserved across species. +2 is a canonical splice site. Nearby pathogenic variants at this codon or neighboring codons: Other variants in this splicing region are present in ClinVar and other canonical splice site variants are called likely pathogenic or pathogenic: c.513+1G>A, c.513+1G>C, c.513+45T>G) Population data: There is no variation at this position listed in 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 33.3x whereas in exomes it is 55.8x.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
