VCV000054028.9 - ClinVar

NM_000492.4(CFTR):c.618G>T (p.Leu206Phe)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance

2 out of 3 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.618G>T (p.Leu206Phe)

Variation ID: 54028 Accession: VCV000054028.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117535286 (GRCh38) [ NCBI UCSC ] 7: 117175340 (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	Feb 16, 2025	Apr 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.618G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Leu206Phe	missense
NC_000007.14:g.117535286G>T
NC_000007.13:g.117175340G>T
NG_016465.4:g.74503G>T
LRG_663:g.74503G>T
LRG_663t1:c.618G>T	LRG_663p1:p.Leu206Phe

... more HGVS ... less HGVS

Protein change

L206F

Other names

Canonical SPDI

NC_000007.14:117535285:G:T

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

ClinGen: CA327603 dbSNP: rs397508770 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	3771	6170

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	Uncertain significance (2)	criteria provided, single submitter	Dec 29, 2018	RCV000576987.10
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 22, 2024	RCV004586523.1

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 (Dec 29, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cystic fibrosis	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001485048.5 First in ClinVar: Mar 07, 2021 Last updated: Feb 16, 2025	Publications: PubMed (2) PubMed: 10923036‚ 11379874 Comment: show 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.Leu206 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID:¬†15776432, 21520337, 23974870, 20021716, 27086061), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 been observed in individuals affected with cystic fibrosis (PMID: 10923036, 11379874). ClinVar contains an entry for this variant (Variation ID: 54028). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 206 of the CFTR protein (p.Leu206Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. (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

Uncertain significance (Apr 22, 2024) 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: SCV005077106.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (2) PubMed: 10923036‚ 11379874 Comment: show Variant summary: CFTR c.618G>T (p.Leu206Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 251446 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.618G>T has been reported in the literature without a zygosity or genotype specification in individuals affected with Cystic Fibrosis (example, Claustres_2000, Le Marchal_2001). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. A different variant affecting the same codon has been classified as pathogenic by our lab (c.617T>G, p.Leu206Trp), supporting the critical relevance of codon 206 to CFTR protein function. 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: 10923036, 11379874). ClinVar contains an entry for this variant (Variation ID: 54028). 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: SCV000679477.1 First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018	Publications: PubMed (1) PubMed: 11379874 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:

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.Leu206 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID:¬†15776432, 21520337, 23974870, 20021716, 27086061), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 been observed in individuals affected with cystic fibrosis (PMID: 10923036, 11379874). ClinVar contains an entry for this variant (Variation ID: 54028). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 206 of the CFTR protein (p.Leu206Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine.

Comment:

Variant summary: CFTR c.618G>T (p.Leu206Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 251446 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.618G>T has been reported in the literature without a zygosity or genotype specification in individuals affected with Cystic Fibrosis (example, Claustres_2000, Le Marchal_2001). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. A different variant affecting the same codon has been classified as pathogenic by our lab (c.617T>G, p.Leu206Trp), supporting the critical relevance of codon 206 to CFTR protein function. 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: 10923036, 11379874). ClinVar contains an entry for this variant (Variation ID: 54028). 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
Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling.	Le Maréchal C	Human genetics	2001	PMID: 11379874
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France.	Claustres M	Human mutation	2000	PMID: 10923036

Text-mined citations for rs397508770 ...

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 Apr 07, 2025