Submissions for variant NM_170707.4(LMNA):c.1698+1G>A

gnomAD frequency: 0.00001  dbSNP: rs1553266337

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001813872	SCV002061100	likely pathogenic	not provided	2024-12-04	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 10939567)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001885299	SCV002270093	likely pathogenic	Charcot-Marie-Tooth disease type 2	2023-07-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 10 of the LMNA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1334358). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV004009160	SCV004829504	uncertain significance	Primary dilated cardiomyopathy	2023-06-28	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 10 of the lamin A transcript (NM_170707.3). Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant is likely to cause an in-frame skipping of exon 10 (90 bp-long). In the lamin C transcript (NM_005572.3), this variant corresponds to c.1699G>A that results in the missense variant (p.Val567Met) at the C-terminal end of the lamin C protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LMNA-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.