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

dbSNP: rs1553266337

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519351	SCV000616764	likely pathogenic	not provided	2024-12-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 10939567)
Color Diagnostics, LLC DBA Color Health	RCV001524187	SCV001733965	uncertain significance	Cardiomyopathy	2023-08-07	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the +1 position of intron 10 of the lamin A transcript (NM_170707.3). Splice prediction tools suggest that this variant may disrupt 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>C that results in the missense variant (p.Val567Leu) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001524187	SCV004099912	likely pathogenic	Cardiomyopathy	2023-09-16	criteria provided, single submitter	clinical testing	Variant summary: LMNA NM_170707.3:c.1698+1G>C is located in a canonical splice-site of the longer transcript and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site that would result in an in-frame skipping of exon 10. However, these predictions have yet to be confirmed by functional studies. This variant also alters an exonic nucleotide, c.1699G>C (p.Val567Leu) located in the last coding exon (exon 10) of another equally expressed shorter transcript NM_005572.3 of the LMNA gene. The variant was absent in 153988 control chromosomes. To our knowledge, no occurrence of c.1698+1G>C or c.1699G>C in individuals affected with Cardiomyopathy/LMNA-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic for the canonical transcript (NM_170707.3) utilized in the context of this evaluation.
PreventionGenetics, part of Exact Sciences	RCV004527626	SCV004105176	likely pathogenic	LMNA-related disorder	2022-09-14	criteria provided, single submitter	clinical testing	The LMNA c.1698+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in LMNA are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581682	SCV004273159	likely pathogenic	Charcot-Marie-Tooth disease type 2	2025-01-26	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: 449051). 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	RCV004806384	SCV005427726	uncertain significance	Primary dilated cardiomyopathy	2024-03-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004992297	SCV005614282	likely pathogenic	Cardiovascular phenotype	2024-07-17	criteria provided, single submitter	clinical testing	The c.1698+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 10 of the LMNA gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.