Submissions for variant NM_000492.4(CFTR):c.1270G>A (p.Gly424Ser)

gnomAD frequency: 0.00012  dbSNP: rs371107552

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000590109	SCV000339832	uncertain significance	not provided	2016-03-14	criteria provided, single submitter	clinical testing
Invitae	RCV000462099	SCV000552133	uncertain significance	Cystic fibrosis	2022-04-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 424 of the CFTR protein (p.Gly424Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with rheumatoid arthritis and bronchiectasis (PMID: 21131649). ClinVar contains an entry for this variant (Variation ID: 286406). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 12732620). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000397807	SCV000696833	uncertain significance	not specified	2023-06-14	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1270G>A (p.Gly424Ser) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, the variant resulted in reduced inclusion of exon 9 in a mini-gene assay (Pagani_2003). The variant allele was found at a frequency of 9.7e-05 in 247386 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (9.7e-05 vs 0.013), allowing no conclusion about variant significance. c.1270G>A has been reported in two affected patients with rheumatoid arthritis and diffuse bronchiectasis (RA-DB) from one family (Puechal_2011) without strong evidence for pathogenicity. The Sickkids database also reports a female patient with bronchiectasis harboring this variant. The variant has also been reported in two patients with pancreatic cancer (Tamura_2018), and in a large Cystic Fibrosis patient cohort (Raraigh_2022). These reports do not provide unequivocal conclusions about association of the variant with Non-Classic Cystic Fibrosis. The following publications have been ascertained in the context of this evaluation (PMID: 23420618, 11504857, 28603918, 15536480, 12732620, 16251901, 21131649, 25735457, 29669919, 34782259). Eleven ClinVar submitters have assessed the variant since 2014: all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000397807	SCV000711288	uncertain significance	not specified	2016-05-20	criteria provided, single submitter	clinical testing	The p.Gly424Ser variant in CFTR has been reported in at least 1 Caucasian indivi dual with diffuse bronchiectasis and rheumatoid arthritis. Multiple members of t his family are reported to be affected, but this variant does not segregate with disease (Puechal 2011). This variant has been identified in 9/57094 European ch romosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs371107552). Computational prediction tools and conservation analysis suggest that the p.Gly424Ser variant may not impact the protein, though this in formation is not predictive enough to rule out pathogenicity. In summary, the cl inical significance of the p.Gly424Ser variant is uncertain.
Counsyl	RCV000462099	SCV000797213	uncertain significance	Cystic fibrosis	2018-01-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590109	SCV000883573	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing	The CFTR c.1270G>A; p.Gly424Ser variant (rs371107552) has been reported in two individuals from a family with rheumatoid arthritis and bronchiectasis (Puechal 2011), and reported to cause exon 9 skipping in a portion of transcripts (Pagani 2003, Aissat 2013). However, this variant occurs in a weakly conserved amino acid (Chen 2001), and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be tolerated. This variant is reported in the ClinVar database as uncertain (Variation ID: 286406), and observed in general population databases with overall allele frequencies of 0.015 percent (2/12966 alleles, Exome Variant Server), and 0.008 percent (21/272812 alleles, Genome Aggregation Database), but is considered a low confidence variant in the database due to segmental duplication. Based on the above information, the clinical significance of p.Gly424Ser is uncertain at this time. REFERENCES Link to ClinVar database for p.Gly424Ser: https://www.ncbi.nlm.nih.gov/clinvar/variation/286406/ Aissat A et al. Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. Hum Mutat. 2013 Jun;34(6):873-81. Chen JM et al. A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models. Mol Biol Evol. 2001 Sep;18(9):1771-88. Pagani F et al. Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. J Biol Chem. 2003 Jul 18;278(29):26580-8. Puechal X et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis. 2011 Apr;70(4):653-9.
Johns Hopkins Genomics, Johns Hopkins University	RCV000462099	SCV001167237	uncertain significance	Cystic fibrosis	2019-10-19	criteria provided, single submitter	clinical testing	This CFTR variant (rs371107552) is rare (<0.1%) in large population datasets1,2 (gnomAD: 24/277606 total alleles; 0.0087%, no homozygotes). Six submitters in ClinVar classify the clinical significance of this variant as uncertain. One study has demonstrated that CFTR c.1270G>A may decrease inclusion of exon 10 (legacy exon 9) during splicing; however, bioinformatics tools do not predict this variant will alter typical splicing patterns. Two bioinformatics tools predict this amino acid substitution will be tolerated. The glycine residue at this position is not well conserved across species assessed. Due to insufficient evidence, we consider the clinical significance of c.1270G>A uncertain at this time.
Ambry Genetics	RCV000462099	SCV001170885	uncertain significance	Cystic fibrosis	2021-12-06	criteria provided, single submitter	clinical testing	The p.G424S variant (also known as c.1270G>A), located in coding exon 10 of the CFTR gene, results from a G to A substitution at nucleotide position 1270. The glycine at codon 424 is replaced by serine, an amino acid with similar properties. This alteration was reported in two related individuals with diffuse bronchiectasis and rheumatoid arthritis; one of the individuals also carried the p.G576A alteration but the phase was unclear (Pu&eacute;chal X. et al., Ann. Rheum. Dis. 2011 Apr; 70(4):653-9). One study of Hep3B cells transfected with this alteration showed some mRNA transcripts with skipping of exon 9 in addition to wild type mRNA transcripts (Pagani F et al., J. Biol. Chem. 2003 Jul; 278(29):26580-8). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000462099	SCV002027397	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000590109	SCV002759167	uncertain significance	not provided	2022-06-02	criteria provided, single submitter	clinical testing	Identified in the single heterozygous state or with a second CFTR variant, phase unknown, in an asymptomatic individual and individuals with bronchiectasis (Puchal et al., 2011; Claustres et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25735457, 12732620, 11504857, 23420618, 21131649, 29669919, 15536480, 16251901, 28603918)
Fulgent Genetics, Fulgent Genetics	RCV002480028	SCV002786365	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-05-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000462099	SCV001456066	uncertain significance	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing