NM_000492.4(CFTR):c.1781T>C (p.Leu594Pro) AND Cystic fibrosis

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 6, 2017
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:: RCV000536733.9

Allele description [Variation Report for NM_000492.4(CFTR):c.1781T>C (p.Leu594Pro)]

NM_000492.4(CFTR):c.1781T>C (p.Leu594Pro)

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.1781T>C (p.Leu594Pro)

HGVS:

NC_000007.14:g.117591948T>C
NG_016465.4:g.131165T>C
NM_000492.4:c.1781T>CMANE SELECT
NP_000483.3:p.Leu594Pro
NP_000483.3:p.Leu594Pro
LRG_663t1:c.1781T>C
LRG_663:g.131165T>C
LRG_663p1:p.Leu594Pro
NC_000007.13:g.117232002T>C
NM_000492.3:c.1781T>C

Protein change:

L594P

Links:

dbSNP: rs1554389245

NCBI 1000 Genomes Browser:

rs1554389245

Molecular consequence:

NM_000492.4:c.1781T>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
SCV000625729	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 6, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] http://www.genet.sikkids.on.a/,
SCV002710361	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 20, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000625729

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 6, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

http://www.genet.sikkids.on.a/,

SCV002710361

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 20, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing.

Schrijver I, Pique L, Graham S, Pearl M, Cherry A, Kharrazi M.

J Mol Diagn. 2016 Jan;18(1):39-50. doi: 10.1016/j.jmoldx.2015.07.005.

PubMed [citation]

PMID:: 26708955

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000625729.3

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

Description

In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been observed with a second pathogenic variant in an individual in the Cystic Fibrosis Mutation Database who was found to have elevated sweat chloride levels and a positive IRT test on newborn screening (http://www.genet.sickkids.on.ca/). 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 disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 594 of the CFTR protein (p.Leu594Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.

#	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 Ambry Genetics, SCV002710361.2

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

Description

The p.L594P pathogenic mutation (also known as c.1781T>C), located in coding exon 14 of the CFTR gene, results from a T to C substitution at nucleotide position 1781. The leucine at codon 594 is replaced by proline, an amino acid with similar properties. In our internal cohort, this mutation has been confirmed in trans with another CFTR mutation in a patient with elevated sweat chloride levels, lung disease, and pancreatic insufficiency. Based on our internal structural analysis, this proline is located in the first nucleotide binding domain (NBD1) of the protein, and it is structurally more destabilizing than known pathogenic variants within this domain. This variant was not reported in the ExAC database, with coverage at this position. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

#	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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