ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.601G>A (p.Val201Met) (rs138338446)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725285 SCV000335701 uncertain significance not provided 2018-02-07 criteria provided, single submitter clinical testing
GeneDx RCV000725285 SCV000568548 uncertain significance not provided 2016-11-02 criteria provided, single submitter clinical testing The V201M variant in the CFTR gene has been reported previously as heterozygous in one child diagnosed with CF; no other variants in the CFTR gene were identified (Bernardino et al., 2000). The V201M variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V201M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Pathogenic missense variants in nearby residues (H199Y, P205S) have been reported in the Human Gene Mutation Database in association with CF (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret V201M as a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000381189 SCV000602985 uncertain significance not specified 2018-07-05 criteria provided, single submitter clinical testing The CFTR c.601G>A; p.Val201Met variant (rs138338446) has been identified without an additional pathogenic variant in an individual with a clinical diagnosis of cystic fibrosis (CF) and individuals with congenital bilateral absence of the vas deferens (CBAVD) (Bernardino 2000, Gallati 2009, Steiner 2011, Wu 2005) and in one individual with CBAVD who also carried a severe pathogenic variant (Steiner 2011). However, this variant is most often identified in individuals with atypical CF as part of a complex variant on the same allele as other variants (Behar 2017, Brugnon 2008, Claustres 2004, Masson 2013, Steiner 2011, Terlizzi 2017). The variant is described in the ClinVar database (Variation ID: 54022). The variant is listed in the general population with an allele frequency of 0.2% (58/277152 alleles) in the Genome Aggregation Database. The valine at this position is moderately conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, the clinical significance of this variant cannot be determined with certainty. REFERENCES Behar DM et al. Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. Bernardino AL et al. Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations. Genet Test. 2000;4(1):69-74. Brugnon F et al. Outcome of intracytoplasmic sperm injection for a couple in which the man is carrier of CFTR p.[R74W;V201M;D1270N] and p.P841R mutations and his spouse a heterozygous carrier of p.F508del mutation of the cystic fibrosis transmembrane conductance regulator gene. Fertil Steril. 2008 Nov;90(5):2004.e23-6. Claustres M et al. Are p.I148T, p.R74W and p.D1270N cystic fibrosis causing mutations? BMC Med Genet. 2004 Aug 2;5:19. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. 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. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. Terlizzi V et al. Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. J Med Genet. 2017 Apr;54(4):224-235. Wu CC et al. Mutation spectrum of the CFTR gene in Taiwanese patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2005 Sep;20(9):2470-5.
Counsyl RCV000666392 SCV000790677 uncertain significance Cystic fibrosis 2017-03-31 criteria provided, single submitter clinical testing
Mendelics RCV000666392 SCV000886151 uncertain significance Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000725285 SCV000889313 uncertain significance not provided 2020-04-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV001024815 SCV001186900 uncertain significance Inborn genetic diseases 2019-01-31 criteria provided, single submitter clinical testing The p.V201M variant (also known as c.601G>A), located in coding exon 6 of the CFTR gene, results from a G to A substitution at nucleotide position 601. The valine at codon 201 is replaced by methionine, an amino acid with highly similar properties. This variant was identified in isolation in a child with mild pulmonary disease, pancreatic sufficiency, and elevated; however, a second alteration was not identified (Bernardino AL et al. Genet. Test., 2000;4:69-74). In a child with a positive newborn screen, elevated sweat chloride levels, and steatorrhea, this variant was identified in conjunction with p.G542*; however, phase was not provided (Mota LR et al. Mol. Biol. Rep., 2018 Sep;45(6):2045–51). It was also identified in isolation in men with congenital absence of the vas deferens (CBAVD), including in one male who was also heterozygous for p.F508del; however, the phase was not confirmed (Danziger KL et al. Hum. Reprod., 2004 Mar;19:540-6; Wu CC et al. Hum. Reprod., 2005 Sep;20:2470-5;Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In addition, this variant has also been observed as part of the complex allele p.[R74W;V201M;D1270N] (de Prada Merino A et al. J. Cyst. Fibros., 2010 Dec;9:447-9). The complex allele has been identified in the homozygous state and in trans with a pathogenic mutation in CFTR in individuals with CBAVD (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). In one report, two young boys carried the complex allele in trans with p.F508del and were asymptomatic; however, CBAVD was not ruled out (Brugnon F et al. Fertil. Steril., 2008 Nov;90:2004.e23-6). 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). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000381189 SCV001362675 uncertain significance not specified 2021-07-05 criteria provided, single submitter clinical testing Variant summary: CFTR c.601G>A (p.Val201Met) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane 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 0.00023 in 253560 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00023 vs 0.013), allowing no conclusion about variant significance. c.601G>A has been widely reported in the literature in sequencing studies among individuals affected with Non-classic Cystic Fibrosis, mainly CBAVD and mild CF phenotypes (example Bernarrdino_2000, Danziger_2004, Wu_2005, Gallati_2009, Tropel_2010, Steiner_2011, Boudaya_2012, Chamayou_2020). These data do not allow unequivocal conclusions about variant significance although the complex allele comprising this variant in cis with c.220C>T (p.Arg74Trp) and c.3808G>A (p.Asp1270Asn) is considered a common disease causing variant combination. At least one recent publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 48% of normal activity in an assay measuring CFTR Function by short-circuit chloride current measurements (Raraigh_2018). The authors report a CFTR2 database classification of this variant in isolation as "indeterminate". Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Majority of the submitters have classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation (VUS, n=1, Pathogenic, n=1). Based on the clinical and functional evidence outlined above, the variant in isolation was classified as a bonafide VUS-possibly pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000666392 SCV001430640 uncertain significance Cystic fibrosis 2020-06-11 criteria provided, single submitter clinical testing CFTR variant of uncertain clinical significance. See www.CFTR2.org for phenotype information.
Invitae RCV000666392 SCV001592096 pathogenic Cystic fibrosis 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 201 of the CFTR protein (p.Val201Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs138338446, ExAC 0.03%), including at least one homozygous and/or hemizygous individual. This variant has been reported as homozygous or in combination with a pathogenic CFTR variant in several individuals affected with cystic fibrosis or congenital bilateral absence of the vas deferens (PMID: 27738188, 21520337, 15287992, 19897426, 25910067, 16963320, 21658649, 30232781, Invitae). In at least one of these individuals, the data is consistent with the variant being in trans (on the opposite allele) from a pathogenic variant. In the literature, this variant is often reported in cis with the benign variants p.Arg74Trp and p.Asp1270Asn (p.[Arg74Trp; Val201Met; Asp1270Asn]). ClinVar contains an entry for this variant (Variation ID: 54022). Experimental studies have shown that this missense change leads to reduced functional activity of the CFTR protein; however, the activity was much higher than that of known null alleles (PMID: 27738188, 21708286). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000725285 SCV001715945 uncertain significance not provided 2019-07-15 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000666392 SCV001781368 uncertain significance Cystic fibrosis 2021-07-14 criteria provided, single submitter clinical testing
Natera, Inc. RCV001027904 SCV001190627 uncertain significance CFTR-related disorders 2019-05-20 no assertion criteria provided clinical testing
Natera, Inc. RCV000666392 SCV001453950 uncertain significance Cystic fibrosis 2018-04-27 no assertion criteria provided clinical testing

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