Submissions for variant NM_000492.4(CFTR):c.2909G>A (p.Gly970Asp)

gnomAD frequency: 0.00001  dbSNP: rs386134230

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046718	SCV000924213	pathogenic	Cystic fibrosis	2018-08-31	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046718	SCV000052160	pathogenic	Cystic fibrosis	2022-10-25	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2909G>A (p.Gly970Asp) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250920 control chromosomes. c.2909G>A has been reported in the literature as biallelic compound heterozygous genotypes in multiple individuals affected with Cystic Fibrosis (example, Wagner_1999, Li_2012, Goubau_2009, McCague_2019, Tian_2016). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Wagner_1999, Amato_2019). The most pronounced variant effect results in 5-12% of normal CFTR channel activity and a partial trafficking defect that were both sensitive to potentiator (VX-770, Ivacaftor) or correctors (VX-809, Lumacaftor and VX-661, Tezacaftor). Seven clinical diagnostic laboratories and an expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000046718	SCV000245589	pathogenic	Cystic fibrosis	2020-01-21	criteria provided, single submitter	clinical testing	The p.Gly970Asp variant in CFTR has been reported in the compound heterozygous state in a least 13 individuals of predominantly Asian ancestry with CFTR-related disorders (10 with cystic fibrosis and 3 with congenital bilateral absence of the vas deferens (CBAVD); Wagner 1999, Wine 2001, Goubau 2009, Li 2012, Tian 2016, Xu 2017, Amato 2019). In at least 10 of these individuals, the second identified variant was pathogenic or likely pathogenic. This variant has also been identified in 0.016% (3/18394) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that this variant impacts protein function (Wagner 1999, Amato 2019) and computational prediction tools and conservation analyses are consistent with pathogenicity. This variant is located in the first base of the exon, which is part of the 3’ splice region. Additional computational tools do not predict altered splicing. Additionally, this variant was classified as pathogenic on August 31st, 2018 by the ClinGen-approved CFTR2 expert panel (Variation ID 35854). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM3_Very Strong, PM2, PP3, PS3_Supporting.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000046718	SCV001160438	pathogenic	Cystic fibrosis	2024-07-09	criteria provided, single submitter	clinical testing	The CFTR c.2909G>A; p.Gly970Asp variant (rs386134230, ClinVar Variation ID: 35854) is reported in the literature in numerous individuals affected with cystic fibrosis (CF) (Goubau 2009, Tian 2016, Wagner 1999, Xu 2017, CFTR2 database). This variant has been observed in affected individuals in trans to other pathogenic variants, and it is primarily associated with pancreatic-sufficient CF (Goubau 2009, Tian 2016, Wagner 1999, CFTR2 database). Additionally, this variant has been observed in individuals with congenital bilateral absence of the vas deferens (CBAVD) (Hou 2023), including those that also carried mild pathogenic variants (Li 2012). This variant is only observed on three alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.985). Consistent with this, the p.Gly970Asp variant protein exhibits 1.7% of wildtype chloride channel activity in CFBE cells (CFTR2 database) and shows decreased efflux activity in HEK cells (Wagner 1999). Additionally, other amino acid substitutions at this codon (p.Gly970Arg, p.Gly970Ser) have been reported in individuals with CF and are considered pathogenic (Ortiz 2017, Sosnay 2012, CFTR2 database). Based on available information, the p.Gly970Asp variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009 Aug;64(8):683-91. PMID: 19318346. Hou JW et al. Loss-of-function CFTR p.G970D missense mutation might cause congenital bilateral absence of the vas deferens and be associated with impaired spermatogenesis. Asian J Androl. 2023 Jan-Feb;25(1):58-65. PMID: 35665694. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 Jul;11(4):316-23. PMID: 22483971. Ortiz SC et al. Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation. Mol Genet Genomic Med. 2017 Nov;5(6):751-757. PMID: 29178639. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870. Tian X et al. p.G970D is the most frequent CFTR mutation in Chinese patients with cystic fibrosis. Hum Genome Var. 2016 Jan 7;3:15063. PMID: 27081564. Wagner JA et al. Two novel mutations in a cystic fibrosis patient of Chinese origin. Hum Genet. 1999 Jun;104(6):511-5. PMID: 10453741. Xu J et al. Four case reports of Chinese cystic fibrosis patients and literature review. Pediatr Pulmonol. 2017 Aug;52(8):1020-1028. PMID: 28608624
Baylor Genetics	RCV001004490	SCV001163535	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046718	SCV001585849	pathogenic	Cystic fibrosis	2024-06-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 970 of the CFTR protein (p.Gly970Asp). This variant is present in population databases (rs386134230, gnomAD 0.02%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 10453741, 22483971, 23302613, 27081564, 28608624). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 35854). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CFTR function (PMID: 28608624). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001781321	SCV002019258	pathogenic	not provided	2022-09-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000046718	SCV002507352	pathogenic	Cystic fibrosis	2022-03-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000046718	SCV002573943	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM3_STR, PM2_SUP, PM5_STR, PP3, PP4
Ambry Genetics	RCV000046718	SCV002750948	pathogenic	Cystic fibrosis	2019-12-20	criteria provided, single submitter	clinical testing	The p.G970D pathogenic mutation (also known as c.2909G>A) is located in coding exon 18 of the CFTR gene. The glycine at codon 970 is replaced by aspartic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 18. This mutation has been reported in multiple Chinese individuals with cystic fibrosis and congenital bilateral absence of the vas deferens, who were described as compound heterozygotes with additional CFTR variants detected; segregation analysis confirming variants were in trans (on different chromosomes) was documented in some cases (Wagner JA et al. Hum. Genet., 1999 Jun;104:511-5; Wine JJ et al. Pediatrics, 2001 Feb;107:280-6; Li H et al. J. Cyst. Fibros., 2012 Jul;11:316-23; Liu JR et al. Zhonghua Er Ke Za Zhi, 2012 Nov;50:829-33; Xu J et al. Pediatr. Pulmonol., 2017 08;52:1020-1028; Huang T et al. Glob Pediatr Health, 2019 Apr;6:2333794X19833725; Amato F et al. Hum. Mutat., 2019 06;40:742-748). Limited functional studies demonstrated trafficking defects and decreased channel activity (Amato F et al. Hum. Mutat., 2019 06;40:742-748), and another functional analysis of this variant in CFBE cells demonstrated 48% activity compared to wild type (Raraigh KS et al. Am J Hum Genet, 2018 06;102:1062-1077). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.001% (3/250920). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473135	SCV004213474	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001781321	SCV005201951	pathogenic	not provided	2023-09-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate p.G970D is functionally impaired compared to wild type (Wagner et al., 1999); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; 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: 32020786, 31036917, 35314707, 22483971, 35894192, 36038301, 23302613, 10453741, 28608624, 32429104, 30420730, 33713579, 37477516, 36604502, 35665694, 32539862, 30851139, 32761997, 32777524)
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001004490	SCV005415698	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PM3_VeryStrong+PP4
Fulgent Genetics, Fulgent Genetics	RCV005042091	SCV005666393	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-05-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000046718	SCV000485692	likely pathogenic	Cystic fibrosis	2016-01-29	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002228059	SCV002507436	pathogenic	CFTR-related disorder	2022-03-25	no assertion criteria provided	clinical testing