ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3468G>A (p.Leu1156=) (rs139729994)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000046899 SCV000677604 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Counsyl RCV000046899 SCV000220434 likely pathogenic Cystic fibrosis 2014-06-19 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000428306 SCV000227776 uncertain significance not provided 2014-12-11 criteria provided, single submitter clinical testing
GeneDx RCV000428306 SCV000521024 pathogenic not provided 2019-03-22 criteria provided, single submitter clinical testing The c.3468G>A (L1156L) variant has been previously reported to cause skipping of exon 21 (referred to as exon 18) in one proband with another pathogenic F508del allele; however, a full publication presenting this data is not available (Zielenski et al, 1994). Other clinical laboratories have observed the c.3468G>A variant in conjunction with other known pathogenic variants in multiple probands with cystic fibrosis, thus supporting its potentially pathogenic role (SCV000227776.1; personal communication with Ambry Genetics). The G to A substitution at nucleotide position 3468 is conserved through mammals and does not change the amino acid at codon 1156; however, it occurs at the last base pair of coding exon 21, adjacent to the splice donor site of intron 21. Variants at these exonic positions can impact mRNA splicing; however, in silico splicing predictors are inconsistent in their predictions as to whether this particular variant alters mRNA splicing.
Ambry Genetics RCV000624739 SCV000742204 likely pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: NEGATIVE - No Relevant Alterations Detected (Step 2)
Mendelics RCV000046899 SCV000886300 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000046899 SCV000992332 pathogenic Cystic fibrosis 2019-11-11 criteria provided, single submitter clinical testing Previously reported disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
CFTR-France RCV001009370 SCV001169223 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Integrated Genetics/Laboratory Corporation of America RCV000046899 SCV001372314 pathogenic Cystic fibrosis 2020-06-18 criteria provided, single submitter clinical testing Variant summary: CFTR c.3468G>A (p.Leu1156Leu) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site and one predicts the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions indicating that the variant causes exon-skipping leading to premature termination and truncation of CFTR (Zielendki_1994). The variant allele was found at a frequency of 4e-06 in 250770 control chromosomes (gnomAD). c.3468G>A has been reported in the literature in compound heterozygous individuals affected with Cystic Fibrosis (e.g. Claustres_2000, Zielendki_1994) while it was also reported in homozygous individuals affected with CBAVD and pancreatitis (e.g. Claustres_2017 & CFTR-France online database). These data indicate that the variant is likely to be associated with disease. Five ClinVar submitters including an expert panel (CFTR2) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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