ClinVar Genomic variation as it relates to human health

The CFTR c.358G>A; p.Ala120Thr variant (rs201958172) has been observed in individuals with cystic fibrosis (CFTR2 database, Chillon 1994, Jalalirad 2004, Padoan 2002, Radivojevic 2004, Sasihuseyinoglu 2019), pancreatitis (Masson 2013), and congenital bilateral absence of vas deferens (Dork 1997). In several individuals with cystic fibrosis, a second pathogenic variant was also identified (Padoan 2002; Sasihuseyinoglu 2019), but a second variant was not reported in many patients carrying p.Ala120Thr. The p.Ala120Thr variant is reported in ClinVar (Variation ID: 53774). The CFTR2 database describes p.Ala120Thr as having varying clinical consequences and those with cystic fibrosis are likely to be pancreatic sufficient (CFTR2 database). This variant is found in the general population with an overall allele frequency of 0.01% (39/282308 alleles) in the Genome Aggregation Database. The alanine at codon 120 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.787). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: CFTR2 database: https://cftr2.org/ Chillon M et al. Analysis of the CFTR gene confirms the high genetic heterogeneity of the Spanish population: 43 mutations account for only 78% of CF chromosomes. Hum Genet. 1994 Apr;93(4):447-51. PMID: 7513293. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 Sep;100(3-4):365-77. PMID: 9272157. Jalalirad M et al. First study of CF mutations in the CFTR gene of Iranian patients: detection of DeltaF508, G542X, W1282X, A120T, R117H, and R347H mutations. J Trop Pediatr. 2004 Dec;50(6):359-61. PMID: 15537723. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 Aug 8;8(8):e73522. PMID: 23951356. Padoan R et al. Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis. Acta Paediatr. 2002;91(1):82-7. PMID: 11883825. Radivojevic D et al. Spectrum of cystic fibrosis mutations in Serbia and Montenegro and strategy for prenatal diagnosis. Genet Test. 2004 Fall;8(3):276-80. PMID: 15727251. Sasihuseyinoglu AS et al. Two years of newborn screening for cystic fibrosis in Turkey: Çukurova experience. Turk J Pediatr. 2019;61(4):505-512. PMID: 31990467.

The p.A120T variant (also known as c.358G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 358. The alanine at codon 120 is replaced by threonine, an amino acid with similar properties. The p.A120T variant (also known as c.358G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 358. The alanine at codon 120 is replaced by threonine, an amino acid with similar properties. This variant was first described in a child with cystic fibrosis (CF) with elevated sweat chloride levels and pancreatic symptoms; however, a second alteration was not identified (Chillón M et al. Hum. Genet., 1994 Apr;93:447-51). This mutation was also detected in an individual with asthma in conjunction with a 5T allele; however, the phase was not provided (Tzetis M et al. Hum. Genet., 2001 Mar;108:216-21). A study of individuals with idiopathic chronic pancreatitis identified one individual with this variant and no other alterations in PRSS1, SPINK1, or CTRC genes (Masson E et al. PLoS ONE, 2013 Aug;8:e73522). This variant was also identified in an individual with congenital bilateral absence of the vas deferens (CBAVD); however, a second alteration was not identified (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). The p.A120T variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 15, 2020). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.

In silico analysis supports that this missense variant does not alter protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 9272157, 15537723, 11354633, 23951356, 27449771, 19318035, 21520337, 22427236, 9439669, 12752573, 7517264, 21198395, 7513293, 15727251, 23523379, 7532150, 17489851, 11883825, 34426522, 31488014, 33572515, 34405919, 33988008, 34996830, 31990467, 31916691, 34525262, 37313453, 35769956, 18687795, 10439967, 28830496)

Variant summary: CFTR c.358G>A (p.Ala120Thr) 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 6.7e-05 in 1618662 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (6.7e-05 vs 0.013), allowing no conclusion about variant significance. The c.358G>A variant has been reported in the literature in heterozygous or presumed compound heterozygous state in several individuals affected with Non-Classic Cystic Fibrosis (example, Chillon_1994, Kanavakis_2003, Radivojevic_2004), as well as CBAVD, asthma, ICP, and lung disease patients, though full genotype information and sweat test results were often not reported or normal, making interpretation difficult. A few studies reported the variant in compound heterozygosity with a known pathogenic variant (p.F508del) in individuals with intermediate or abnormal sweat chloride test values, with at least one of them affected with pancreatic insufficiency and another one affected with recurrent pneumonia (example, De Wachter_2017, Sasihuiseyinoglu_2019, Munck_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 46.73% of normal chloride channel conductance relative to wild type (example, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 31488014, 21198395, 9439669, 7513293, 7517264, 28830496, 9272157, 15537723, 12752573, 10439967, 23951356, 31916691, 11883825, 15727251, 22427236, 31990467, 21520337, 17489851, 11354633, 38388235). ClinVar contains an entry for this variant (Variation ID: 53774). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 120 of the CFTR protein (p.Ala120Thr). This variant is present in population databases (rs201958172, gnomAD 0.04%). This missense change has been observed in individual(s) with cystic fibrosis, congenital absence of the vas deferens or chronic pancreatitis (PMID: 7513293, 7517264, 9272157, 10439967, 18687795, 23951356, 33572515). ClinVar contains an entry for this variant (Variation ID: 53774). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

The frequency of this variant in the general population, 0.00043 (13/30578 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported with varying clinical consequences in individuals with cystic fibrosis (PMIDs: 31990467 (2019), 15537723 (2004), 15727251 (2004), 12752573 (2003), 10439967 (1999), 7517264 (1994)), and individuals without cystic fibrosis (PMIDs: 22427236 (2013), 21520337 (2011), 17489851 (2007), 11883825 (2002)). Additionally, the variant has been reported in individuals with pancreatic insufficiency (PMID: 28830496 (2017)), idiopathic chronic pancreatitis (PMID: 23951356 (2013), and congenital absence of the vas deferens (PMID: 9272157 (1997)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging.

CFTR: PM1, PM2, PM3:Supporting

This variant was identified in 2 unrelated patients 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: PM2_SUP, PM3, PM5, PP3