VCV002573422.2 - ClinVar

NM_000492.4(CFTR):c.1070C>T (p.Ala357Val)

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.1070C>T (p.Ala357Val)

Variation ID: 2573422 Accession: VCV002573422.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117540300 (GRCh38) [ NCBI UCSC ] 7: 117180354 (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	Jul 29, 2023	Feb 20, 2024	Jun 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1070C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Ala357Val	missense
NC_000007.14:g.117540300C>T
NC_000007.13:g.117180354C>T
NG_016465.4:g.79517C>T
LRG_663:g.79517C>T
LRG_663t1:c.1070C>T	LRG_663p1:p.Ala357Val

... more HGVS ... less HGVS

Protein change

A357V

Other names

Canonical SPDI

NC_000007.14:117540299:C:T

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.

Links

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	-	-

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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Jun 26, 2023	RCV003317758.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Mar 20, 2023	RCV003738430.1

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 (Jun 26, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004020655.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (2) PubMed: 31523618‚ 36437957 Comment: Variant summary: CFTR c.1070C>T (p.Ala357Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: CFTR c.1070C>T (p.Ala357Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251054 control chromosomes (gnomAD). c.1070C>T has been reported in the literature in individuals affected with Cystic Fibrosis and Congenital absence of the vas deferens (examples: Terzic_2019 and Fang_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36437957, 31523618). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
Uncertain significance (Mar 20, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004564483.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: The CFTR c.1070C>T; p.Ala357Val variant is reported in an individual with a mild CF phenotype, who carried F508del on the opposite allele (Terzic 2019). This … (more) The CFTR c.1070C>T; p.Ala357Val variant is reported in an individual with a mild CF phenotype, who carried F508del on the opposite allele (Terzic 2019). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.646). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Terzic M et al. Cystic Fibrosis Mutation Spectrum in North Macedonia: A Step Toward Personalized Therapy. Balkan J Med Genet. 2019 Aug 28;22(1):35-40. PMID: 31523618. (less)

Comment:

Variant summary: CFTR c.1070C>T (p.Ala357Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251054 control chromosomes (gnomAD). c.1070C>T has been reported in the literature in individuals affected with Cystic Fibrosis and Congenital absence of the vas deferens (examples: Terzic_2019 and Fang_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36437957, 31523618). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Comment:

The CFTR c.1070C>T; p.Ala357Val variant is reported in an individual with a mild CF phenotype, who carried F508del on the opposite allele (Terzic 2019). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.646). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Terzic M et al. Cystic Fibrosis Mutation Spectrum in North Macedonia: A Step Toward Personalized Therapy. Balkan J Med Genet. 2019 Aug 28;22(1):35-40. PMID: 31523618.

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
Congenital absence of the vas deferens with hypospadias or without hypospadias: Phenotypic findings and genetic considerations.	Fang J	Frontiers in genetics	2022	PMID: 36437957
Cystic Fibrosis Mutation Spectrum in North Macedonia: A Step Toward Personalized Therapy.	Terzic M	Balkan journal of medical genetics : BJMG	2019	PMID: 31523618

Text-mined citations for this variant ...

Record last updated Feb 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.1070C>T (p.Ala357Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...