NM_000492.4(CFTR):c.3406G>A (p.Ala1136Thr) AND Cystic fibrosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 5, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001223100.5

Allele description [Variation Report for NM_000492.4(CFTR):c.3406G>A (p.Ala1136Thr)]

NM_000492.4(CFTR):c.3406G>A (p.Ala1136Thr)

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.3406G>A (p.Ala1136Thr)

HGVS:

NC_000007.14:g.117614651G>A
NG_016465.4:g.153868G>A
NM_000492.4:c.3406G>AMANE SELECT
NP_000483.3:p.Ala1136Thr
LRG_663t1:c.3406G>A
LRG_663:g.153868G>A
NC_000007.13:g.117254705G>A
NC_000007.13:g.117254705G>A
NM_000492.3:c.3406G>A

Protein change:

A1136T

Links:

dbSNP: rs755968404

NCBI 1000 Genomes Browser:

rs755968404

Molecular consequence:

NM_000492.4:c.3406G>A - 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
SCV001395234	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 5, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9164328, 21520337, 22483971, 23951356, 27706244, 33937153, 35119551, 36437957, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001395234

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 5, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Pistachio-green stools and anaemia in infancy: early signs of cystic fibrosis?

Jakobson AM.

Lancet. 1997 May 17;349(9063):1452. No abstract available.

PubMed [citation]

PMID:: 9164328

Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.

Steiner B, Rosendahl J, Witt H, Teich N, Keim V, Schulz HU, Pfützer R, Löhr M, Gress TM, Nickel R, Landt O, Koudova M, Macek M Jr, Farre A, Casals T, Desax MC, Gallati S, Gomez-Lira M, Audrezet MP, Férec C, des Georges M, Claustres M, et al.

Hum Mutat. 2011 Aug;32(8):912-20. doi: 10.1002/humu.21511. Epub 2011 Jun 7. Erratum in: Hum Mutat. 2012 Feb;33(2):456. Lühr, Matthias [corrected to Löhr, Matthias].

PubMed [citation]

PMID:: 21520337

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001395234.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1136 of the CFTR protein (p.Ala1136Thr). This variant is present in population databases (rs755968404, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with chronic pancreatitis, congenital absence of the vas deferens, cystic fibrosis, and/or intrahepatic cholestasis (PMID: 9164328, 21520337, 22483971, 23951356, 27706244, 33937153, 35119551, 36437957). ClinVar contains an entry for this variant (Variation ID: 951237). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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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