Submissions for variant NM_000492.4(CFTR):c.3461A>G (p.Asp1154Gly)

dbSNP: rs397508569

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR-France	RCV001009503	SCV001169598	pathogenic	CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235017	SCV003934548	uncertain significance	not specified	2023-05-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3461A>G (p.Asp1154Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 4e-06 in 250930 control chromosomes. c.3461A>G has been reported in the literature as a non-informative genotype (second allele not specified) in individuals affected with CBAVD/CAVD and Cystic Fibrosis (Claustres_2000, Green_2010, Yang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis/CFTR-related disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired chloride channel activity (Vankeerberghen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 10923036, 20932301, 9804160, 26277102). CFTR-France database has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV004700332	SCV005201953	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Observed in at least one individual with congenital absence of the vas deferens who also harbored a second CFTR variant, but segregation data and additional clinical information was not included (Claustres et al., 2000; Costes et al., 1995; De Braekeleer et al., 1996); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28603918, 20059485, 9804160, 31674704, 8556303, 9239681, 16442101, 12940920, 10923036)
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577763	SCV000679055	not provided	Cystic fibrosis		no assertion provided	literature only