Submissions for variant NM_000492.4(CFTR):c.1352G>T (p.Gly451Val)

dbSNP: rs1554382653

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV004702286	SCV005201947	uncertain significance	not provided	2023-10-31	criteria provided, single submitter	clinical testing	Reported on the same chromosome (in cis) as p.(Gly253Arg) in heterozygous or homozygous state in multiple individuals with cystic fibrosis from Ecuador, but additional clinical information and familial segregation information was not included (PMID: 30763667); Not observed at significant frequency in large population cohorts (gnomAD); 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: 32596391, 32429104, 16189704, 35698092, 30763667)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702287	SCV005204831	uncertain significance	not specified	2024-06-11	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1352G>T (p.Gly451Val) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244264 control chromosomes. c.1352G>T has been reported in the literature in the heterozygous, presumed compound heterozygous, and complex presumed compound heterozygous (sharing an allele with another rare VUS p.Gly253Arg) states in multiple individuals affected with Cystic Fibrosis and/or CFTR-related conditions (example, McGinness_2005, Petrova_2020, Rueda-Nieto_2022, Ruiz-Cabezas_2019, Shen_2022, Woodall_2021, Woodall_2023). The impact of the complex allele consisting of c.[757G>A;1352G>T] p.[(Gly253Arg;Gly451Val)] may be pathogenic as it has been seen in several individuals affected with cystic fibrosis-spectrum disease with various presumed compound heterozygous pathogenic variants on the second allele (example, Ruiz-Cabezas_2019), however the impact of p.Gly451Val alone cannot be disambiguated. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16189704, 32429104, 35698092, 30763667, 35858753, 34613844, 37701179). ClinVar contains an entry for this variant (Variation ID: 553569). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005034250	SCV005673318	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-06-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000669047	SCV000793746	uncertain significance	Cystic fibrosis	2017-08-30	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].