ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1270G>A (p.Gly424Ser) (rs371107552)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590109 SCV000339832 uncertain significance not provided 2016-03-14 criteria provided, single submitter clinical testing
Invitae RCV000462099 SCV000552133 uncertain significance Cystic fibrosis 2019-08-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 424 of the CFTR protein (p.Gly424Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. The frequency data for this variant (rs371107552) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in 2 individuals from a family with rheumatoid arthritis and bronchiectasis (PMID: 21131649). ClinVar contains an entry for this variant (Variation ID: 286406). An experimental study has shown that this variant results in reduced inclusion of exon 9 (also known as exon 10 by alternate exon numbering) in minigene assays, compared to the wild-type (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.
Integrated Genetics/Laboratory Corporation of America RCV000397807 SCV000696833 uncertain significance not specified 2019-04-25 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 of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, a mini-gene assay reported the variant to result in reduced exon 9 inclusion (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 expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (9.7e-05 vs 0.013), allowing no conclusion about variant significance. This variant was reported in two affected patients with rheumatoid arthritis and diffuse bronchiectasis (RA-DB) from a family (Puechal_2011) without a strong evidence for pathogenicity. The Sickkids database also reports the variant in a female patient with bronchiectasis. In addition, the variant has been reported in two patients with pancreatic cancer (Tamura_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare 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 ( 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: 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 RCV001010655 SCV001170885 uncertain significance Inborn genetic diseases 2019-02-21 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Insufficient or conflicting evidence;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)

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