Submissions for variant NM_000492.4(CFTR):c.1439G>A (p.Gly480Asp)

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV001507709	SCV001713414	likely pathogenic	not provided	2020-10-26	criteria provided, single submitter	clinical testing	PM2, PM5, PP3, PP5
Baylor Genetics	RCV003473455	SCV004213454	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-07-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767041	SCV005381186	pathogenic	Cystic fibrosis	2024-08-13	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1439G>A (p.Gly480Asp) results in a non-conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251304 control chromosomes (gnomAD). c.1439G>A has been reported in the literature in compound heterozygous individuals affected with Cystic Fibrosis (e.g. Behar_2017, Lopes_2023), who carried a second pathogenic variant. These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1438G>T, p.Gly480Cys), supporting the critical relevance of codon 480 to CFTR protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately (Gt channel conductance) 0.34% 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: 38388235, 28546993, 36437230). ClinVar contains an entry for this variant (Variation ID: 53255). Based on the evidence outlined above, the variant was classified as pathogenic.

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