NM_000492.4(CFTR):c.4141T>C (p.Tyr1381His) AND Cystic fibrosis

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Aug 25, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000577023.5

Allele description [Variation Report for NM_000492.4(CFTR):c.4141T>C (p.Tyr1381His)]

NM_000492.4(CFTR):c.4141T>C (p.Tyr1381His)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.4141T>C (p.Tyr1381His)

HGVS:

NC_000007.14:g.117665463T>C
NG_016465.4:g.204680T>C
NM_000492.4:c.4141T>CMANE SELECT
NP_000483.3:p.Tyr1381His
NP_000483.3:p.Tyr1381His
LRG_663t1:c.4141T>C
LRG_663:g.204680T>C
LRG_663p1:p.Tyr1381His
NC_000007.13:g.117305517T>C
NM_000492.3:c.4141T>C

Protein change:

Y1381H

Links:

dbSNP: rs397508682

NCBI 1000 Genomes Browser:

rs397508682

Molecular consequence:

NM_000492.4:c.4141T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000679136	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000791126	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 2, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002627228	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 25, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18782298, 31005549 Citation Link,
SCV003260810	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18782298, 28492532

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Summary from all submissions

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

Citations

PubMed

Cystic fibrosis screen positive inconclusive diagnosis (CFSPID): Experience in Tuscany, Italy.

Terlizzi V, Mergni G, Buzzetti R, Centrone C, Zavataro L, Braggion C.

J Cyst Fibros. 2019 Jul;18(4):484-490. doi: 10.1016/j.jcf.2019.04.002. Epub 2019 Apr 18.

PubMed [citation]

PMID:: 31005549

Identification and characterization of CFTR gene mutations in Indian CF patients.

Sharma N, Singh M, Kaur G, Thapa BR, Prasad R.

Ann Hum Genet. 2009 Jan;73(1):26-33. doi: 10.1111/j.1469-1809.2008.00477.x. Epub 2008 Sep 8.

PubMed [citation]

PMID:: 18782298

See all PubMed Citations (3)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679136.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	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 Counsyl, SCV000791126.1

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

From Ambry Genetics, SCV002627228.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Y1381H variant (also known as c.4141T>C), located in coding exon 26 of the CFTR gene, results from a T to C substitution at nucleotide position 4141. The tyrosine at codon 1381 is replaced by histidine, an amino acid with similar properties. This variant was identified in conjunction with p.F508del in two individuals; one individual was reported to have cystic fibrosis while the other was healthy with normal sweat chloride levels (Sharma N et al. Ann Hum Genet, 2009 Jan;73:26-33; Terlizzi V et al. J Cyst Fibros, 2019 07;18:484-490). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003260810.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces tyrosine with histidine at codon 1381 of the CFTR protein (p.Tyr1381His). The tyrosine residue is weakly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 18782298). ClinVar contains an entry for this variant (Variation ID: 53900). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

#	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

Last Updated: Sep 29, 2024

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