Submissions for variant NM_170707.4(LMNA):c.1969-1G>T

dbSNP: rs1060499873

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455558	SCV000539537	uncertain significance	not specified	2016-08-12	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Predicted to impact splicing of last exon, not previously reported
Color Diagnostics, LLC DBA Color Health	RCV001188692	SCV001355818	uncertain significance	Cardiomyopathy	2023-06-14	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 11 of the LMNA gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in a frameshift in the penultimate exon of the lamin A protein and addition of 46 new amino acids before introducing a stop codon. This would result in a protein product that is 2 amino acids longer than the normal protein product. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001303566	SCV001492815	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-05-11	criteria provided, single submitter	clinical testing	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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 403042). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 11 of the LMNA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
GeneDx	RCV003441856	SCV004169048	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant with an unclear effect on protein function; Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance
All of Us Research Program, National Institutes of Health	RCV004000603	SCV004832699	uncertain significance	Primary dilated cardiomyopathy	2023-06-26	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 11 of the LMNA gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in a frameshift in the penultimate exon of the lamin A protein and addition of 46 new amino acids before introducing a stop codon. This would result in a protein product that is 2 amino acids longer than the normal protein product. 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.