Submissions for variant NM_000492.4(CFTR):c.3854C>T (p.Ala1285Val)

dbSNP: rs397508617

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585919	SCV000696994	uncertain significance	not specified	2022-04-12	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3854C>T (p.Ala1285Val) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 0.00066 in 250862 control chromosomes (gnomAD), predominantly at a frequency of 0.0053 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is somewhat lower than the maximum expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence of the Vas Deferens (CBAVD) (0.013), allowing no conclusion about variant significance. c.3854C>T has been reported in the literature in at least two Asian Indian individuals affected with CBAVD, however no second (likely) pathogenic variant was specified in these cases (Sachdeva 2011, Gaikwad_2020). The variant was also found during carrier screening in homozygosity in an Asian Indian (Schwartz_2009) and an Australian individual (Archibald_2017), but no phenotype information was provided. These reports do not provide unequivocal conclusions about association of the variant with CBAVD. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance, one as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507714	SCV001713438	uncertain significance	not provided	2021-07-14	criteria provided, single submitter	clinical testing
Invitae	RCV000577447	SCV001721256	benign	Cystic fibrosis	2024-01-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001507714	SCV002046548	uncertain significance	not provided	2022-12-29	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0053 (162/30594 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 21254931 (2011), 34145097 (2020)) and in an individual with pancreatitis (PMID: 33097431 (2020)). The variant has also been reported in carrier screenings (PMID: 19324992 (2009), 29261177 (2018), 30146269 (2019), 32784480 (2020), 32906206 (2020), 33138774 (2020)). 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. Based on the available information, we are unable to determine the clinical significance of this variant.
Johns Hopkins Genomics, Johns Hopkins University	RCV000577447	SCV002051796	likely benign	Cystic fibrosis	2021-09-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000577447	SCV002622766	likely benign	Cystic fibrosis	2023-04-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV001507714	SCV003831650	uncertain significance	not provided	2023-04-06	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003448254	SCV004176470	uncertain significance	Hereditary pancreatitis	2023-03-01	criteria provided, single submitter	clinical testing	The missense c.3854C>T (p.Ala1285Val) variant in CFTR gene has been reported previously in heterozygous state in individual(s) affected with SPINK1-associated Chronic Pancreatitis (Jones et al., 2020). This variant is reported with the allele frequency of 0.06% in the gnomAD Exomes. This variant has been reported to the ClinVar database with varying interpretation: Benign / Likely Benign / Uncertain Significance (multiple submitters). The amino acid Ala at position 1285 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala1285Val in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. SPINK1 carriers with co-occurring mutations in CFTR exhibited prominent fibrosis of the pancreas and only focal intralobular and/or extralobular lipomatous infiltration into the pancreatic parenchyma. For these reasons, this variant has been classified as Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004537230	SCV004720028	likely benign	CFTR-related disorder	2022-02-09	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577447	SCV000679387	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV000577447	SCV001460116	uncertain significance	Cystic fibrosis	2017-05-09	no assertion criteria provided	clinical testing