NM_000492.4(CFTR):c.1196C>T (p.Ala399Val) AND Cystic fibrosis

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Jul 12, 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:: RCV000669005.9

Allele description [Variation Report for NM_000492.4(CFTR):c.1196C>T (p.Ala399Val)]

NM_000492.4(CFTR):c.1196C>T (p.Ala399Val)

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.1196C>T (p.Ala399Val)

HGVS:

NC_000007.14:g.117542095C>T
NG_016465.4:g.81312C>T
NM_000492.4:c.1196C>TMANE SELECT
NP_000483.3:p.Ala399Val
NP_000483.3:p.Ala399Val
LRG_663t1:c.1196C>T
LRG_663:g.81312C>T
LRG_663p1:p.Ala399Val
NC_000007.13:g.117182149C>T
NM_000492.3:c.1196C>T

Protein change:

A399V

Links:

dbSNP: rs146463120

NCBI 1000 Genomes Browser:

rs146463120

Molecular consequence:

NM_000492.4:c.1196C>T - 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
SCV000793699	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Aug 28, 2017)	unknown	clinical testing	Citation Link,
SCV001781363	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 14, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002646650	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 21, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003785171	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 12, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20460946, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

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

CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation.

Pelletier AL, Bienvenu T, Rebours V, O'Toole D, Hentic O, Maire F, Hammel P, Ruszniewski P, Lévy P.

Pancreatology. 2010;10(2-3):158-64. doi: 10.1159/000231976. Epub 2010 May 12.

PubMed [citation]

PMID:: 20460946

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000793699.1

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

From Genome-Nilou Lab, SCV001781363.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002646650.2

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

Description

The p.A399V variant (also known as c.1196C>T), located in coding exon 9 of the CFTR gene, results from a C to T substitution at nucleotide position 1196. The alanine at codon 399 is replaced by valine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with idiopathic pancreatitis (Pelletier AL et al. Pancreatology, 2010 May;10:158-64). 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003785171.2

#	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 alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 399 of the CFTR protein (p.Ala399Val). This variant is present in population databases (rs146463120, gnomAD 0.06%). This missense change has been observed in individual(s) with idiopathic pancreatitis (PMID: 20460946). ClinVar contains an entry for this variant (Variation ID: 495889). 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: Nov 3, 2024

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