NM_000492.4(CFTR):c.929TCT[2] (p.Phe312del) AND Cystic fibrosis

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Oct 14, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000047290.25

Allele description [Variation Report for NM_000492.4(CFTR):c.929TCT[2] (p.Phe312del)]

NM_000492.4(CFTR):c.929TCT[2] (p.Phe312del)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.929TCT[2] (p.Phe312del)

Other names:

[delta]F311

HGVS:

NC_000007.13:g.117180219_117180221delTCT
NC_000007.14:g.117540159TCT[2]
NG_016465.4:g.79376TCT[2]
NM_000492.4:c.929TCT[2]MANE SELECT
NP_000483.3:p.Phe312del
LRG_663t1:c.935_937del
LRG_663:g.79376TCT[2]
NC_000007.13:g.117180211_117180213del
NC_000007.13:g.117180213TCT[2]
NC_000007.13:g.117180219_117180221del
NC_000007.13:g.117180219_117180221delTCT
NC_000007.14:g.117540165_117540167del
NM_000492.3:c.933_935delCTT
NM_000492.3:c.935_937delTCT
NM_000492.4:c.935_937delMANE SELECT

Protein change:

F312del

Links:

dbSNP: rs121908768

NCBI 1000 Genomes Browser:

rs121908768

Molecular consequence:

NM_000492.4:c.929TCT[2] - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV000697058	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 10, 2022)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 15371903, 12007216, 15858154, 12394352, 9443874, 11388756, 7509232, 22311127, 16980811, 26574590, 26847993, 28801929, 16617247, 31672438, 31665830, 31036917, 32630227 Citation Link,
SCV001132361	Counsyl	no assertion criteria provided	Likely pathogenic (May 26, 2017)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 26098992, 10923036, 15371903, 26574590, 18788470, 15300780, 26708955, 9443874, 22311127, 7509232
SCV001582745	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 14, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7509232, 9443874, 16980811, 26098992, 28492532
SCV002686349	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 31, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12007216, 27912062, 7509232 Citation Link,
SCV004024540	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum.

Schrijver I, Ramalingam S, Sankaran R, Swanson S, Dunlop CL, Keiles S, Moss RB, Oehlert J, Gardner P, Wassman ER, Kammesheidt A.

J Mol Diagn. 2005 May;7(2):289-99.

PubMed [citation]

PMID:: 15858154
PMCID:: PMC1867528

Standards and guidelines for CFTR mutation testing.

Richards CS, Bradley LA, Amos J, Allitto B, Grody WW, Maddalena A, McGinnis MJ, Prior TW, Popovich BW, Watson MS, Palomaki GE.

Genet Med. 2002 Sep-Oct;4(5):379-91. Erratum in: Genet Med. 2002 Nov-Dec;4(6):471..

PubMed [citation]

PMID:: 12394352

See all PubMed Citations (25)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697058.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

Variant summary: CFTR c.935_937delTCT (p.Phe312del) results in an in-frame deletion that is predicted to remove one phenylalanine from three consecutive phenylalanines, located in the first transmembrane region (IPR011527) of the encoded protein. The variant allele was found at a frequency of 7.6e-05 in 251076 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.013), allowing no conclusion about variant significance. The variant (also known as deltaF311) has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Meitinger_1993, Friedman_1998, Heim_2001, Watts_2012, Kharrazi_2015, Taccetti_2020). 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. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic (n=2) / likely pathogenic (n=2). 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 Counsyl, SCV001132361.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001582745.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant, c.935_937del, results in the deletion of 1 amino acid(s) of the CFTR protein (p.Phe312del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758477732, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with cystic fibrosis (PMID: 7509232, 9443874, 16980811, 26098992). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as deltaF311. ClinVar contains an entry for this variant (Variation ID: 48704). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

From Ambry Genetics, SCV002686349.2

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

Description

The p.F312del pathogenic mutation (also known as c.935_937delTCT, c.933_935delCTT and deltaF311 in the literature) is located in coding exon 8 of the CFTR gene. This mutation results from an in-frame deletion of 3 nucleotides at positions 935 to 937. This results in the deletion of a phenylalanine (F) residue at codon 312, within a string of F residues (codons 310 through 312). In a meta-analysis of worldwide mutation incidence, this mutation was observed in 0.2% of all cystic fibrosis (CF) alleles, and in 2.0% of African American CF alleles (Bobadilla JL et al. Hum. Mutat. 2002;19(6):575-606). In one study, this mutation was detected in trans with p.F508del in a 2-year-old patient with growth retardation who was noted to have repeated elevated sweat chloride levels, but unremarkable lung and gastrointestinal symptoms (Meitinger T et al. Hum Mol Genet. 1993;2(12):2173-2174). Another study detected this mutation in a Hispanic CF patient, but no further clinical data was provided (Schrijver I et al. J Mol Diagn. 2005;7(2):289-299). We have observed this mutation in either the homozygous or compound heterozygous state in CF patients in our clinical cohort. In addition, our internal structural analysis revealed that F312 is a part of the transmembrane loop 5 and loss of this residue results in disruptive shift of amino acids in the loop (Zhang Z et al. Cell, 2016 Dec;167:1586-1597.e9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 Johns Hopkins Genomics, Johns Hopkins University, SCV004024540.2

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

Description

CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.

#	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: Dec 7, 2024

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