ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2846A>T (p.His949Leu) (rs397508444)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000577071 SCV001137488 likely pathogenic Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000577071 SCV001425365 uncertain significance Cystic fibrosis 2020-05-08 criteria provided, single submitter clinical testing CFTR c.2846A>T has been identified an individual with an equivocal sweat chloride concentration. There is an entry in ClinVar for this variant and it (rs397508444) is rare (<0.1%) in a large population dataset (gnomAD: 5/282786 total alleles; 0.0018%; no homozygotes). Three bioinformatic tools queried predict that this substitution would probably be damaging and the histidine residue at this position is evolutionarily conserved across all species assessed. c.2846A>T has been reported as part of a complex allele on the same chromosome as c.2816A>G in multiple individuals. This patient does not carry this complex allele, as only c.2846A>T is present. Due to insufficient evidence, we consider the clinical significance of c.2846C>T to be uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290523 SCV001478575 uncertain significance not specified 2021-01-08 criteria provided, single submitter clinical testing Variant summary: CFTR c.2846A>T (p.His949Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2846A>T has been reported in the literature in at-least one individual with atypical CF and equivocal sweat chloride levels (example, McGinniss_2005). It has also been reported as a complex allele in cis with p.H949L and another disease causing CF variant in trans (i.e., compound heterozygous genotype) in patients with CF (at-least four ascertainments) and CFTR-RD (at-least one ascertainment) (example, Polizzi_2011, Diana_2016, Paganin_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis in isolation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. One submitter has cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577071 SCV000679010 not provided Cystic fibrosis no assertion provided literature only

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