VCV000053924.4 - ClinVar

NM_000492.4(CFTR):c.422C>A (p.Ala141Asp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.422C>A (p.Ala141Asp)

Variation ID: 53924 Accession: VCV000053924.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117531047 (GRCh38) [ NCBI UCSC ] 7: 117171101 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 25, 2018	May 1, 2024	Jan 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.422C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Ala141Asp	missense
NC_000007.14:g.117531047C>A
NC_000007.13:g.117171101C>A
NG_016465.4:g.70264C>A
LRG_663:g.70264C>A
LRG_663t1:c.422C>A	LRG_663p1:p.Ala141Asp
	P13569:p.Ala141Asp

... more HGVS ... less HGVS

Protein change

A141D

Other names

Canonical SPDI

NC_000007.14:117531046:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00000

Links

ClinGen: CA327458 UniProtKB: P13569#VAR_000127 dbSNP: rs397508700 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CFTR		-	-	GRCh38 GRCh37	3826	5201

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cystic fibrosis	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 25, 2024	RCV000577350.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jan 25, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005035779.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 10834512‚ 32429104‚ 9222768 Comment: The p.A141D variant (also known as c.422C>A), located in coding exon 4 of the CFTR gene, results from a C to A substitution at nucleotide … (more) The p.A141D variant (also known as c.422C>A), located in coding exon 4 of the CFTR gene, results from a C to A substitution at nucleotide position 422. The alanine at codon 141 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals diagnosed with cystic fibrosis (Gouya L et al. Hum Mutat, 1997;10:86-7; Kambouris M et al. Eur J Pediatr, 2000 May;159:303-9; Petrova NV et al. Genes (Basel), 2020 May;11:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
Likely pathogenic (Oct 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001167215.1 First in ClinVar: Mar 08, 2020 Last updated: Mar 08, 2020	Comment: This CFTR variant is absent from large population datasets. This variant is present in ClinVar by one submitter, however a classification was not provided. Multiple … (more) This CFTR variant is absent from large population datasets. This variant is present in ClinVar by one submitter, however a classification was not provided. Multiple patients have been reported to carry this variant along with a second disease-causing CFTR variant; in one of these cases the variants were confirmed to be on opposite chromosomes (in trans). Of two bioinformatics tools queried, one predicts that the substitution would be possibly damaging, while the second predicts that it would be tolerated. The alanine residue at this position is highly evolutionarily conserved across most species assessed. We consider this variant likely pathogenic. (less)
Likely pathogenic (Jan 03, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004295537.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 9222768‚ 30548586‚ 32429104 Comment: This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 141 of the CFTR protein … (more) This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 141 of the CFTR protein (p.Ala141Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9222768, 30548586, 32429104). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53924). 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 expected to disrupt CFTR protein function with a positive 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. (less)
not provided (-)	no classification provided Method: literature only	CFTR-related disorders Affected status: yes Allele origin: germline	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000679148.1 First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018	Publications: PubMed (1) PubMed: 9222768

Comment:

The p.A141D variant (also known as c.422C>A), located in coding exon 4 of the CFTR gene, results from a C to A substitution at nucleotide position 422. The alanine at codon 141 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals diagnosed with cystic fibrosis (Gouya L et al. Hum Mutat, 1997;10:86-7; Kambouris M et al. Eur J Pediatr, 2000 May;159:303-9; Petrova NV et al. Genes (Basel), 2020 May;11:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

Comment:

This CFTR variant is absent from large population datasets. This variant is present in ClinVar by one submitter, however a classification was not provided. Multiple patients have been reported to carry this variant along with a second disease-causing CFTR variant; in one of these cases the variants were confirmed to be on opposite chromosomes (in trans). Of two bioinformatics tools queried, one predicts that the substitution would be possibly damaging, while the second predicts that it would be tolerated. The alanine residue at this position is highly evolutionarily conserved across most species assessed. We consider this variant likely pathogenic.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 141 of the CFTR protein (p.Ala141Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9222768, 30548586, 32429104). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53924). 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 expected to disrupt CFTR protein function with a positive 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.	Petrova NV	Genes	2020	PMID: 32429104
Comprehensive genotyping reveals novel CFTR variants in cystic fibrosis patients from the Russian Federation.	Petrova NV	Clinical genetics	2019	PMID: 30548586
Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations.	Kambouris M	European journal of pediatrics	2000	PMID: 10834512
Novel mutation (A141D) in exon 4 of the CFTR gene identified in an Algerian patient.	Gouya L	Human mutation	1997	PMID: 9222768

Text-mined citations for rs397508700 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.422C>A (p.Ala141Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397508700 ...