NM_000492.4(CFTR):c.313A>C (p.Ile105Leu) AND Cystic fibrosis

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 3, 2023
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:: RCV001921011.7

Allele description [Variation Report for NM_000492.4(CFTR):c.313A>C (p.Ile105Leu)]

NM_000492.4(CFTR):c.313A>C (p.Ile105Leu)

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.313A>C (p.Ile105Leu)

HGVS:

NC_000007.14:g.117530938A>C
NG_016465.4:g.70155A>C
NM_000492.3:c.313A>C
NM_000492.4:c.313A>CMANE SELECT
NP_000483.3:p.Ile105Leu
LRG_663t1:c.313A>C
LRG_663:g.70155A>C
NC_000007.13:g.117170992A>C

Protein change:

I105L

Links:

dbSNP: rs758675549

NCBI 1000 Genomes Browser:

rs758675549

Molecular consequence:

NM_000492.4:c.313A>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
SCV002197105	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 21, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25697318, 26574590, 27214204, 28830496, 20657600, 28492532
SCV005035736	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 3, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002197105

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 21, 2021)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV005035736

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 3, 2023)

germline

clinical testing

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

[CFTR gene sequencing in a group of Chilean patients with cystic fibrosis].

Lay-Son R G, Vásquez D M, Puga Y A, Manque M P, Repetto L G.

Rev Chil Pediatr. 2014 Jul;85(4):448-54. doi: 10.4067/S0370-41062014000400007. Spanish.

PubMed [citation]

PMID:: 25697318

Newborn Screening for Cystic Fibrosis in California.

Kharrazi M, Yang J, Bishop T, Lessing S, Young S, Graham S, Pearl M, Chow H, Ho T, Currier R, Gaffney L, Feuchtbaum L; California Cystic Fibrosis Newborn Screening Consortium..

Pediatrics. 2015 Dec;136(6):1062-72. doi: 10.1542/peds.2015-0811. Epub 2015 Nov 16.

PubMed [citation]

PMID:: 26574590

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002197105.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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. This variant disrupts the p.Ile105 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: PMID: 25697318, 26574590, 27214204, 28830496, 20657600, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CFTR-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with leucine at codon 105 of the CFTR protein (p.Ile105Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine.

#	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, SCV005035736.1

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

Description

The p.I105L variant (also known as c.313A>C), located in coding exon 4 of the CFTR gene, results from an A to C substitution at nucleotide position 313. The isoleucine at codon 105 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Last Updated: Sep 29, 2024

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