ClinVar Miner

Submissions for variant NM_000344.3(SMN1):c.835-3C>T (rs772466166)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586221 SCV000696579 uncertain significance not provided 2016-10-24 criteria provided, single submitter clinical testing Variant summary: The SMN1 c.835-3C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, Vezain_2011 showed that c.835-3C>T leads to 20% of exon 7 skipping in SMN1 mRNA using minigene assay. In addition, this paper showed full length/exon7 skipped SMN1 mRNA ratio in a patient with mild SMA phenotype, who also carries an exon 7 deletion allele, is higher than the controls with no SMN1 copy and lower than the control with one SMN1 copy. 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. This variant was found in 2/120368 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic SMN1 variant (0.0025). Since only one SMA patient has been reported to carry this variant and the pathogenic role of small amount of exon 7 skipping is not clear, this variant is classified as VUS-possibly pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000785808 SCV000924376 pathogenic Adult spinal muscular atrophy 2016-03-02 criteria provided, single submitter clinical testing
Invitae RCV000798141 SCV000937741 uncertain significance Spinal muscular atrophy 2018-10-10 criteria provided, single submitter clinical testing

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