ClinVar Miner

Submissions for variant NM_000344.4(SMN1):c.835-3C>T

gnomAD frequency: 0.00001  dbSNP: rs772466166
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290445 SCV000696579 uncertain significance not specified 2021-01-26 criteria provided, single submitter clinical testing Variant summary: SMN1 c.835-3C>T alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, at least two functional studies report this variant produced aberrant transcripts (Vezain_2011, Soucek_2019). Additionally, Vezain_2011 showed that this variant leads to 20% of exon 7 skipping in SMN1 mRNA using a minigene assay. This study showed full length/exon7 skipped SMN1 mRNA ratio of 1.8 in a patient with mild SMA phenotype (who also carries an exon 7 deletion allele), which is higher than the positive controls with no SMN1 copy (1) and lower than the healthy controls with one SMN1 copy (2.4). These results further demonstrate that the variant of interest induces exon 7 skipping. However, the pathogenic role of this effect is not clear due to small sample size of patients and lack of additional functional studies. The variant allele was found at a frequency of 8.1e-06 in 248152 control chromosomes (gnomAD). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware RCV000785808 SCV000924376 pathogenic Spinal muscular atrophy, type IV 2016-03-02 criteria provided, single submitter clinical testing
Invitae RCV000798141 SCV000937741 pathogenic Spinal muscular atrophy 2022-03-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 21542063, 31213135). ClinVar contains an entry for this variant (Variation ID: 495829). This variant has been observed in individual(s) with spinal muscular atrophy (SMA) (PMID: 21542063; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This sequence change falls in intron 7 of the SMN1 gene. It does not directly change the encoded amino acid sequence of the SMN1 protein. It affects a nucleotide within the consensus splice site.
Athena Diagnostics Inc RCV000586221 SCV001476123 uncertain significance not provided 2020-06-25 criteria provided, single submitter clinical testing

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