VCV000054038.2 - ClinVar

NM_000492.4(CFTR):c.673T>C (p.Cys225Arg)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Uncertain significance

1 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.673T>C (p.Cys225Arg)

Variation ID: 54038 Accession: VCV000054038.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117535341 (GRCh38) [ NCBI UCSC ] 7: 117175395 (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 3, 2025	Mar 4, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.673T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Cys225Arg	missense
NC_000007.14:g.117535341T>C
NC_000007.13:g.117175395T>C
NG_016465.4:g.74558T>C
LRG_663:g.74558T>C
LRG_663t1:c.673T>C	LRG_663p1:p.Cys225Arg
	P13569:p.Cys225Arg

... more HGVS ... less HGVS

Protein change

C225R

Other names

Canonical SPDI

NC_000007.14:117535340:T:C

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), exomes 0.00000

Links

ClinGen: CA327620 UniProtKB: P13569#VAR_000137 dbSNP: rs397508780 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		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	3800	6217

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	not provided (1)	no classification provided	-	RCV000577637.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Mar 4, 2025	RCV005406779.1

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.	Expand all rows Collapse all rows 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 (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV006070732.1 First in ClinVar: May 03, 2025 Last updated: May 03, 2025	Publications: PubMed (3) PubMed: 1379210‚ 38388235‚ 9374552 Comment: show Variant summary: CFTR c.673T>C (p.Cys225Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.673T>C has been reported in the literature in at-least one individual affected with Cystic Fibrosis (Fanen_1992). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately (Gt channel conductance) 70% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024) and the expression of this variant was moderately reduced in HeLa cells (Fanen_1997). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 1379210, 9374552). ClinVar contains an entry for this variant (Variation ID: 54038). Based on the evidence outlined above, the variant was classified as uncertain significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

not provided (-) N Not contributing to aggregate classification	no classification provided	CFTR-related disorders	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000679505.1 First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018	Publications: PubMed (1) PubMed: 9374552 Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes Observation 1 Collection method: literature only Allele origin: germline Affected status: yes

Comment:

Variant summary: CFTR c.673T>C (p.Cys225Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.673T>C has been reported in the literature in at-least one individual affected with Cystic Fibrosis (Fanen_1992). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately (Gt channel conductance) 70% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024) and the expression of this variant was moderately reduced in HeLa cells (Fanen_1997). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 1379210, 9374552). ClinVar contains an entry for this variant (Variation ID: 54038). Based on the evidence outlined above, the variant was classified as uncertain significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
In vitro modulator responsiveness of 655 CFTR variants found in people with cystic fibrosis.	Bihler H	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2024	PMID: 38388235
Cystic fibrosis phenotype associated with pancreatic insufficiency does not always reflect the cAMP-dependent chloride conductive pathway defect. Analysis of C225R-CFTR and R1066C-CFTR.	Fanen P	The Journal of biological chemistry	1997	PMID: 9374552
Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions.	Fanen P	Genomics	1992	PMID: 1379210

Text-mined citations for rs397508780 ...

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 May 17, 2025