ClinVar

Description

Variant summary: CFTR c.2173G>A (p.Glu725Lys) results in a conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251338 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0001 vs 0.013), allowing no conclusion about variant significance. c.2173G>A has been reported in the literature as a non-informative genotype (second allele and/or zygosity not specified or second allele of uncertain/questionable pathogenicity) in individuals with atypical and variably expressive sub-phenotypic or sub clinical presentations of Cystic Fibrosis (CF) (example, Gene_2008, Kanavakis_2003, Larriba_2005, Girardet_2015, Pall_2007, Audrezat_2008, Hekim_2016, Grangeia_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. Multiple reports of co-occurrences in cis with another pathogenic variant in the CFTR gene (legacy name c.1766+5G>A, also named c.1898+5G>A) with a fully informative genotype in obligate carrier parents and/or CF-chromosomes (Girardet_2015, des Georges_2004) have been reported (ACMG BP2). Additionally, an instance of a co-occurring pathogenic variant in a different gene (SPINK1 c.194+2T>C), in an individual affected with Chronic Pancreatitis (Zou_2018) has also been reported (ACMG BP5). These reports provide supporting evidence for a benign/non-causative role in settings of autosomal recessive Cystic Fibrosis or autosomal dominant SPINK1 associated Pancreatitis. One publication qualitatively reports that double mutants including the variant had no effect on maturation of the CFTR protein (Chen_2002). However, this study does not allow convincing conclusions about the variant effect in isolation. The following publications have been ascertained in the context of this evaluation (PMID: 18687795, 12361483, 18306312, 24762087, 29589582, 27195969, 12752573, 16128988, 17719933, 25735457, 11950844, 30420730, 15698946). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=7; P/LP, n=3). Most submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, although this variant meets at-least two supportive criteria given in the ACMG classification guidance, namely BP2 and BP5, the variant was classified as VUS-possibly benign.