NM_000492.4(CFTR):c.2735C>A (p.Ser912Ter) AND Cystic fibrosis

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Mar 17, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000046665.15

Allele description [Variation Report for NM_000492.4(CFTR):c.2735C>A (p.Ser912Ter)]

NM_000492.4(CFTR):c.2735C>A (p.Ser912Ter)

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.2735C>A (p.Ser912Ter)

HGVS:

NC_000007.14:g.117603609C>A
NG_016465.4:g.142826C>A
NM_000492.4:c.2735C>AMANE SELECT
NP_000483.3:p.Ser912Ter
NP_000483.3:p.Ser912Ter
LRG_663t1:c.2735C>A
LRG_663:g.142826C>A
LRG_663p1:p.Ser912Ter
NC_000007.13:g.117243663C>A
NM_000492.3:c.2735C>A
p.Ser912X

Protein change:

S912*

Links:

dbSNP: rs121909034

NCBI 1000 Genomes Browser:

rs121909034

Molecular consequence:

NM_000492.4:c.2735C>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000245894	CFTR2 - CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Mar 17, 2017)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000487036	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Sep 28, 2016)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7505693, 23974870, 25910067 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000886263	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Nov 5, 2018)	unknown	clinical testing	Citation Link,
SCV001448325	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 12, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9459003, 16931591, 29944384, 30888834, 27812499, 7505693 Citation Link,
SCV001578233	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 9, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7505693, 23974870, 25910067, 1695717, 7691345, 9725922, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	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

Genetic history of cystic fibrosis mutations in Italy. I. Regional distribution.

Rendine S, Calafell F, Cappello N, Gagliardini R, Caramia G, Rigillo N, Silvetti M, Zanda M, Miano A, Battistini F, Marianelli L, Taccetti G, Diana MC, Romano L, Romano C, Giunta A, Padoan R, Pianaroli A, Raia V, De Ritis G, Battistini A, Grzincich G, et al.

Ann Hum Genet. 1997 Sep;61(Pt 5):411-24.

PubMed [citation]

PMID:: 9459003

A new insertion/deletion of the cystic fibrosis transmembrane conductance regulator gene accounts for 3.4% of cystic fibrosis mutations in Sardinia: implications for population screening.

Faà V, Bettoli PP, Demurtas M, Zanda M, Ferri V, Cao A, Rosatelli MC.

J Mol Diagn. 2006 Sep;8(4):499-503.

PubMed [citation]

PMID:: 16931591
PMCID:: PMC1867619

See all PubMed Citations (12)

Details of each submission

From CFTR2 - CFTR2, SCV000245894.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000487036.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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 Mendelics, SCV000886263.2

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001448325.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: CFTR c.2735C>A (p.Ser912X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251374 control chromosomes (gnomAD). c.2735C>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example: Saba_1993, Rendine_1997, Guigui_2016, Faa_2006, McCague_2019, Desai_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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, SCV001578233.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 53550). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7505693, 23974870, 25910067). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser912*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 29, 2024

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