Submissions for variant NM_000492.4(CFTR):c.1312A>G (p.Thr438Ala)

gnomAD frequency: 0.00021  dbSNP: rs201434579

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000436508	SCV000224843	uncertain significance	not provided	2018-08-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000265349	SCV000466512	uncertain significance	CFTR-related disorder	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000436508	SCV000510886	benign	not provided	2016-06-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001589052	SCV001822045	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255311	SCV002529671	benign	Hereditary pancreatitis	2021-07-22	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000436508	SCV001552749	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CFTR p.Thr438Ala variant was not identified in the Cosmic or MutDB databases but was identified in dbSNP (ID: rs201434579), ClinVar (reported as a VUS by Emory and Illumina and benign by the Center for Pediatric Genomic Medicine at the Children's Mercy Hospital and Clinics), Clinvitae and LOVD 3.0. The variant was identified in control databases in 910 of 243424 chromosomes at a frequency of 0.003738 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 184 of 18116 chromosomes (freq: 0.01016), European (Finnish) in 195 of 20214 chromosomes (freq: 0.009647), Other in 46 of 6026 chromosomes (freq: 0.007634), European (non-Finnish) in 407 of 108932 chromosomes (freq: 0.003736), East Asian in 26 of 18052 chromosomes (freq: 0.00144), Latino in 42 of 33100 chromosomes (freq: 0.001269) and Ashkenazi Jewish in 10 of 9894 chromosomes (freq: 0.001011), but was not observed in the South Asian population. Trujillano et al. (2015) identified this variant in the heterozygous state in 1/177 cystic fibrosis patients but suggested the variant to be neutral (Trujillano_2015_PMID: 26436105). The p.Thr438 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV000265349	SCV005355193	uncertain significance	CFTR-related disorder	2024-03-21	no assertion criteria provided	clinical testing	The CFTR c.1312A>G variant is predicted to result in the amino acid substitution p.Thr438Ala. This variant has been reported in a heterozygous state in an individual with cystic fibrosis although it is unknown if a second variant was detected (Trujillano et al. 2015. PMID: 26436105). This variant is reported in 1.0% of alleles in individuals of African descent in gnomAD; however, part of the data set did not pass the quality metrics so this data should be interpreted with caution. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.