Submissions for variant NM_000492.4(CFTR):c.1951G>A (p.Asp651Asn)

gnomAD frequency: 0.00003  dbSNP: rs780526529

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001785765	SCV001174451	uncertain significance	Cystic fibrosis	2021-11-19	criteria provided, single submitter	clinical testing	The p.D651N variant (also known as c.1951G>A), located in coding exon 14 of the CFTR gene, results from a G to A substitution at nucleotide position 1951. The aspartic acid at codon 651 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in an individual with lung cancer; a second CFTR variant was not reported (Bombieri C et al. Hum. Genet., 1998 Dec;103:718-22). In was also identified in a cohort of individuals with cystic fibrosis; however, complete genotype and phenotype information was not provided (Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206). In a minigene assay, this variant showed increase use of cryptic splice sites compared to wildtype (Aznarez I et al. Hum. Mol. Genet., 2003 Aug;12:2031-40). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192401	SCV001360492	uncertain significance	not specified	2019-10-14	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1951G>A (p.Asp651Asn) results in a conservative amino acid change located in the CFTR regulator domain 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 3.2e-05 in 250960 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1951G>A has been reported in the literature in individuals affected with Cystic Fibrosis (Soltysova_2017) and Lung Cancer (Bombieri_1998) . These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. A functional study, Aznarez_2003, found the variant to enhance altered splicing, however, wild type was still being produced and the exact implications of these findings were not fully assessed therefore, not allowing for convincing conclusions about the variant effect. 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	RCV001785765	SCV002027434	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Invitae	RCV001785765	SCV003476566	uncertain significance	Cystic fibrosis	2021-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 651 of the CFTR protein (p.Asp651Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs780526529, ExAC 0.01%). This variant has been observed in individual(s) with clinical features consistent with cystic fibrosis and/or pulmonary disease (PMID: 9921909, 28544683). ClinVar contains an entry for this variant (Variation ID: 820398). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 31159747). 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.	RCV001827184	SCV002080692	uncertain significance	CFTR-related disorders	2018-11-28	no assertion criteria provided	clinical testing