ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1766+5G>T (rs121908796)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000046468 SCV000677595 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Invitae RCV000046468 SCV000074481 pathogenic Cystic fibrosis 2018-12-22 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs121908796, ExAC 0.02%). This variant has been reported in individuals affected with cystic fibrosis (PMID: 7543385, 12874665), and it has been reported to segregate with cystic fibrosis in affected families (PMID: 7543385, 10925568). This variant is considered to be a common CFTR variant in East Asian populations (PMID: 18456578). It is also known as c.1898+5G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 48685). 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 and results in a transcript lacking exon 12 (PMID: 23381846, 7543385). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000046468 SCV000677936 likely pathogenic Cystic fibrosis 2015-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000046468 SCV000696872 pathogenic Cystic fibrosis 2016-07-08 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1766+5G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 4/5 splicing algorithms predict the weakening or elimination of the splice donor site of exon 13. This prediction is confirmed by cDNA studies performed on RNA isolated from a homozygous patient, showing >95% of transcripts lacking exon 13. This variant was found in 2/119622 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). c.1766+5G>T has been cited in numerous CF patients reported in the literature in both compound heterozygous and homozygous states. Taken together, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000046468 SCV000712857 likely pathogenic Cystic fibrosis 2017-02-10 criteria provided, single submitter clinical testing The c.1766+5G>T (NM_000492.3 c.1766+5G>T) variant in CFTR has been reported in 1 homozygous and 3 compound heterozygous Asian individuals with clinical features of cystic fibrosis (Zielenski 1995, Leung 2016, Shen 2016). This variant has be en identified in 0.023% (2/8,562) of East Asian chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121908796). This variant is located in the 3' splice region. Computational tools suggest a possib le impact to splicing consistent with the +5 position being predominantly a G nu cleotide. In summary, the clinical significance of the c.1766+5G>T variant is li kely pathogenic based upon biallelic case observations, suggestive splicing impa ct and low frequency in the general population.

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