ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.4124A>C (p.His1375Pro)

dbSNP: rs397508678
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000757787 SCV000924278 pathogenic Cystic fibrosis 2018-08-31 reviewed by expert panel research
Mendelics RCV000757787 SCV000886161 pathogenic Cystic fibrosis 2019-09-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000757787 SCV005035957 pathogenic Cystic fibrosis 2023-12-27 criteria provided, single submitter clinical testing The p.H1375P pathogenic mutation (also known as c.4124A>C), located in coding exon 25 of the CFTR gene, results from an A to C substitution at nucleotide position 4124. The histidine at codon 1375 is replaced by proline, an amino acid with similar properties. This alteration has been identified in the homozygous and compound heterozygous state in multiple individuals with a clinical diagnosis of cystic fibrosis (Lucarelli M et al. Mol Med, 2015 Apr;21:257-75; Almaghamsi T et al. Saudi Med J, 2023 Oct;44:987-994). This variant has <10% of wild type function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 12/26/2023). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000757787 SCV005381803 pathogenic Cystic fibrosis 2024-08-26 criteria provided, single submitter clinical testing Variant summary: CFTR c.4124A>C (p.His1375Pro) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251220 control chromosomes. c.4124A>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Lucarelli_2015, Almaghamsi_2023, Pennati_2019, Lucarelli_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 16% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 25910067, 30819810, 37777263, 38388235, 28736296). ClinVar contains an entry for this variant (Variation ID: 53895). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000757787 SCV001454296 pathogenic Cystic fibrosis 2020-09-16 no assertion criteria provided clinical testing

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