NM_000492.4(CFTR):c.3274T>C (p.Tyr1092His) AND not provided

Germline classification:: Conflicting classifications of pathogenicity (5 submissions)
Last evaluated:: Jul 14, 2025
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000588214.24

Allele description [Variation Report for NM_000492.4(CFTR):c.3274T>C (p.Tyr1092His)]

NM_000492.4(CFTR):c.3274T>C (p.Tyr1092His)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
CFTR-AS2:CFTR antisense RNA 2 [Gene - HGNC]
LOC111674472:DNase I hypersensitive sites in introns 16 and 17a of CFTR [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.3274T>C (p.Tyr1092His)

HGVS:

NC_000007.14:g.117611715T>C
NG_016465.4:g.150932T>C
NG_056128.2:g.4769T>C
NM_000492.4:c.3274T>CMANE SELECT
NP_000483.3:p.Tyr1092His
NP_000483.3:p.Tyr1092His
LRG_663t1:c.3274T>C
LRG_663:g.150932T>C
LRG_663p1:p.Tyr1092His
NC_000007.13:g.117251769T>C
NM_000492.3:c.3274T>C
p.Tyr1092His

Protein change:

Y1092H

Links:

dbSNP: rs376968326

Molecular consequence:

NM_000492.4:c.3274T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000859316	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Jan 22, 2018)	germline	clinical testing	Citation Link,
SCV001472777	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Jan 14, 2021)	germline	clinical testing	Citation Link,
SCV001714250	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 2, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001780144	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Feb 11, 2020)	germline	clinical testing	Citation Link,
SCV007110890	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	pathogenic (Jul 14, 2025)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 38388235, 27728908, 26990548, 25735457, 35273129, 32734384, 34140271, 36828084, 23687349, 25087612, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

In vitro modulator responsiveness of 655 CFTR variants found in people with cystic fibrosis.

Bihler H, Sivachenko A, Millen L, Bhatt P, Patel AT, Chin J, Bailey V, Musisi I, LaPan A, Allaire NE, Conte J, Simon NR, Magaret AS, Raraigh KS, Cutting GR, Skach WR, Bridges RJ, Thomas PJ, Mense M.

J Cyst Fibros. 2024 Jul;23(4):664-675. doi: 10.1016/j.jcf.2024.02.006. Epub 2024 Feb 22.

PubMed [citation]

PMID:: 38388235

See all PubMed Citations (12)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000859316.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001472777.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The CFTR c.3274T>C; p.Tyr1092His variant (rs376968326) is reported in the literature in the compound heterozygous state with a known pathogenic variant in individuals affected with cystic fibrosis (Prontera 2016, Trujillano 2013). This variant is reported in ClinVar (Variation ID: 495930), and is only observed on seven alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 1092 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the limited clinical data and lack of functional data, the significance of the p.Tyr1092His variant is uncertain at this time. References: Prontera P et al. A Clinical and Molecular Survey of 62 Cystic Fibrosis Patients from Umbria (Central Italy) Disclosing a High Frequency (2.4%) of the 2184insA Allele: Implications for Screening. Public Health Genomics. 2016;19(6):336-341. Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013;50(7):455-462.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001714250.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From GeneDx, SCV001780144.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis supports that this missense variant does not alter protein structure/function; Observed with a pathogenic variant in an individual with cystic fibrosis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Prontera 2016); This variant is associated with the following publications: (PMID: 23687349, 27728908, 25087612)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV007110890.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The CFTR c.3274T>C (p.Tyr1092His) variant has been reported in the published literature in individuals affected with cystic fibrosis (PMIDs: 35273129 (2022), 27728908 (2016)). Individuals affected with cystic fibrosis were compound heterozygous for the variant and another pathogenic CFTR variant ( PMID: 27728908 (2016), and CFTR France (https://cftr.chu-montpellier.fr)). In addition, this variant has been reported as having a deleterious effect on protein function (PMID: 38388235 (2024)). 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, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 7, 2026

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