Submissions for variant NM_000492.4(CFTR):c.484A>G (p.Lys162Glu)

dbSNP: rs397508731

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000757854	SCV000886358	uncertain significance	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001532116	SCV001747523	likely pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000757854	SCV001822003	likely pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000757854	SCV002570335	likely pathogenic	Cystic fibrosis	2022-09-06	criteria provided, single submitter	clinical testing	CFTR c.484A>G has been identified in multiple individuals with features of cystic fibrosis who have a second disease-associated CFTR variant. This CFTR variant (rs397508731) is rare (<0.1%) in a large population dataset (gnomAD: 1/152202 total alleles; 0.0007%; no homozygotes) and has an entry in ClinVar (Variation ID: 53968). BayPR, an algorithm that uses population data to assign disease liability to variants, predicts that this variant is likely to be CF-causing. In addition, two bioinformatic tools queried predict that this amino acid substitution would be damaging and the lysine residue at this position is evolutionarily conserved across all species assessed. We consider CFTR c.484A>G to be likely pathogenic.
Invitae	RCV000757854	SCV003509663	pathogenic	Cystic fibrosis	2023-08-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CFTR protein function. ClinVar contains an entry for this variant (Variation ID: 53968). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 27214204, 30232781, 32674983; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 162 of the CFTR protein (p.Lys162Glu).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000757854	SCV004223574	likely pathogenic	Cystic fibrosis	2023-11-09	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.484A>G (p.Lys162Glu) results in a conservative amino acid change to a highly conserved residue (HGMD) 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 was absent in 247592 control chromosomes (gnomAD). c.484A>G has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Kanavakis_2003, Salinas_2016, Mota_2018, Souza_2021), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12752573, 27214204, 30232781, 32674983, 32819855). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely pathogenic (n=4) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.