Submissions for variant NM_000492.4(CFTR):c.1681G>A (p.Ala561Thr)

dbSNP: rs1226880376

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001785764	SCV001173185	uncertain significance	Cystic fibrosis	2023-04-27	criteria provided, single submitter	clinical testing	The p.A561T variant (also known as c.1681G>A), located in coding exon 13 of the CFTR gene, results from a G to A substitution at nucleotide position 1681. The alanine at codon 561 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in a cohort of individuals with recurrent and/or chronic pediatric pancreatitis (Giefer MJ et al. J. Pediatr., 2017 07;186:95-100). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192433	SCV001360548	uncertain significance	not specified	2019-03-18	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1681G>A (p.Ala561Thr) results in a non-conservative amino acid change located in the ATPase 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 245214 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1681G>A has been reported in the literature in an individual affected with acute recurrent- or chronic pancreatitis (Giefer 2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV001785764	SCV002027423	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Invitae	RCV001785764	SCV002160075	uncertain significance	Cystic fibrosis	2022-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 561 of the CFTR protein (p.Ala561Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatitis (PMID: 28502372). ClinVar contains an entry for this variant (Variation ID: 819812). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Ala561 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14623323, 23891399, 30996306). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Natera, Inc.	RCV001827180	SCV002080648	uncertain significance	CFTR-related disorders	2018-12-26	no assertion criteria provided	clinical testing