ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.137C>T (p.Ala46Val) (rs151020603)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000728272 SCV000855825 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing
Mendelics RCV000757789 SCV000886163 likely pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780112 SCV000917156 uncertain significance not specified 2017-09-22 criteria provided, single submitter clinical testing Variant summary: The c.137C>T (p.Ala46Val) in CFTR gene is a missense variant involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome, however no functional studies supporting these predictions were published at the time of evaluation. The c.137C>T is present in the control population datasets of ExAC and gnomAD at a low frequency of 0.00004 (5/119380 and 14/ 276484 chrs tested, respectively, exclusively in African subpopulation). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0129, suggesting that it is not a common polymorphism. To our knowledge, the variant has not been reported in affected individuals via peer-reviewed reports, but is mentioned to be identified in at least one affected individual with positive newborn screen test, who also carried F508del (phase is unknown). In addition, alteration of the same codon, c.137C>A (p.Ala46Asp) has been identified in Cf-patients and is reported as pathogenic by several laboratories, including However, the variant of interest, c.137C>T is cited as VUS by reputable databases/clinical laboratories. Taken together, due to the lack of supportive evidence, the variant was classified as VUS, until new information becomes available.
Invitae RCV000757789 SCV000944038 uncertain significance Cystic fibrosis 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 46 of the CFTR protein (p.Ala46Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs151020603, ExAC 0.05%). This variant has not been reported in the literature in individuals with CFTR-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Johns Hopkins Genomics, Johns Hopkins University RCV000757789 SCV001167244 uncertain significance Cystic fibrosis 2019-10-19 criteria provided, single submitter clinical testing CFTR c.137C>T has not been reported in the literature, to our knowledge. This CFTR variant (rs151020603) is rare (<0.1%) in a large population dataset1 (gnomAD: 12/282150 total alleles; 0.004%; no homozygotes). There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Three submitters classified it as a variant of uncertain clinical significance and one as likely pathogenic. Two bioinformatic tools queried predict that this substitution would be damaging, and the alanine residue at this position is highly evolutionarily conserved across all species assessed. This variant is located within the same residue as p.Ala46Asp, a previously reported alternate pathogenic missense variant. We consider the clinical significance of c.137C>T uncertain at this time.
Nilou-Genome Lab RCV000757789 SCV001821979 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV001592932 SCV001821980 uncertain significance Congenital bilateral aplasia of vas deferens from CFTR mutation 2021-07-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000757789 SCV001464070 uncertain significance Cystic fibrosis 2020-09-16 no assertion criteria provided clinical testing

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