ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.273G>C (p.Gly91=) (rs773739166)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000587955 SCV000696895 likely pathogenic Cystic fibrosis 2016-06-01 criteria provided, single submitter clinical testing Variant summary: The CFTR c.273G>C (p.Gly91Gly) variant involves the alteration of the last nucleotide of exon 3, resulting in a synonymous change. One in silico tool predicts damaging outcome for this variant. 4/5 splice prediction tools predict that this variant significantly abolishe or weaken the 3' splicing donor site. This prediction has been confirmed by cDNA analysis in a 9-year-old CF patient (Tomaiuolo_2015), who had positive sweat chloride test and pancreatitis. The variant of interest is absent in 120908 control chromosomes from ExAC. One reputable database has classified it as disease-causing. Taken together, this variant is classified as a Likely Pathogenic.
Invitae RCV000587955 SCV001385257 likely pathogenic Cystic fibrosis 2019-05-20 criteria provided, single submitter clinical testing This sequence change affects codon 91 of the CFTR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CFTR protein. This variant also falls at the last nucleotide of exon 3 of the CFTR coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with CFTR-related conditions (PMID: 25636364, 27264265). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 495909). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 25636364). 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.

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