ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1381-5G>A (rs730880133)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157297 SCV000207029 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-07-21 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764983 SCV000896162 uncertain significance Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Benign scapuloperoneal muscular dystrophy with cardiomyopathy; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy 2; Mandibuloacral dysostosis; Lethal tight skin contracture syndrome; Congenital muscular dystrophy, LMNA-related; Emery-Dreifuss muscular dystrophy 3, autosomal recessive 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000484067 SCV000574093 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing The c.1381-5 G>A variant of uncertain significance in the LMNA gene has been reported previously by another clinical laboratory in one individual with hypertrophic cardiomyopathy (HCM), though no clinical details or segregation data were provided (SCV000207029.1, Landrum et al., 2014; Ito et al., 2017). Additionally, this variant has been identified in multiple individuals referred for cardiomyopathy, arrhythmia, or whole exome genetic testing at GeneDx. However, thus 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. The c.1381-5 G>A variant was observed in 0.01-0.02% of alleles from individuals of various ethnic backgrounds in large population cohorts (Lek et al., 2016). The c.1381-5 G>A variant is predicted to create a strong cryptic splice acceptor site located three nucleotides upstream of the canonical splice acceptor site in intron 7. Using a mini-gene assay, Ito et al. (2017) identified aberrant splice product resulting from the c.1381-5 G>A variant and classified it as a variant of uncertain significance. However, it is unclear whether this assay replicates in vivo conditions and further description of the aberrant splice product observed was not provided.
Invitae RCV000815746 SCV000956215 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-11-09 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. This variant is present in population databases (rs730880133, ExAC 0.06%). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 28679633). ClinVar contains an entry for this variant (Variation ID: 180405). Experimental studies have shown that this sequence change results in aberrant 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.

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