NM_000492.4(CFTR):c.2042A>T (p.Glu681Val) AND Cystic fibrosis

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Nov 10, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV001273210.16

Allele description [Variation Report for NM_000492.4(CFTR):c.2042A>T (p.Glu681Val)]

NM_000492.4(CFTR):c.2042A>T (p.Glu681Val)

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.2042A>T (p.Glu681Val)

HGVS:

NC_000007.14:g.117592209A>T
NG_016465.4:g.131426A>T
NM_000492.4:c.2042A>TMANE SELECT
NP_000483.3:p.Glu681Val
NP_000483.3:p.Glu681Val
LRG_663t1:c.2042A>T
LRG_663:g.131426A>T
LRG_663p1:p.Glu681Val
NC_000007.13:g.117232263A>T
NM_000492.3:c.2042A>T
NM_000492.4:c.2042A>T

Protein change:

E681V

Links:

dbSNP: rs201295415

NCBI 1000 Genomes Browser:

rs201295415

Molecular consequence:

NM_000492.4:c.2042A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

Recent activity

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IFIT5 interferon induced protein with tetratricopeptide repeats 5 [Homo sapiens]
IFIT5 interferon induced protein with tetratricopeptide repeats 5 [Homo sapiens]
Gene ID:24138

Gene
(24138[uid]) AND 9606[taxid] AND alive[Properties] AND (alive[pro... (1)
(24138[uid]) AND 9606[taxid] AND alive[Properties] AND (alive[prop])
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001174878	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Nov 10, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18703788, 23514810, 29173301, 29997923, 30811104 Citation Link,
SCV001455986	Natera, Inc.	no assertion criteria provided	Uncertain significance (Apr 23, 2018)	germline	clinical testing
SCV002027436	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002988491	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 7, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29173301, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	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

Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome.

Kim RD, Greenberg DE, Ehrmantraut ME, Guide SV, Ding L, Shea Y, Brown MR, Chernick M, Steagall WK, Glasgow CG, Lin J, Jolley C, Sorbara L, Raffeld M, Hill S, Avila N, Sachdev V, Barnhart LA, Anderson VL, Claypool R, Hilligoss DM, Garofalo M, et al.

Am J Respir Crit Care Med. 2008 Nov 15;178(10):1066-74. doi: 10.1164/rccm.200805-686OC. Epub 2008 Aug 14.

PubMed [citation]

PMID:: 18703788
PMCID:: PMC2720143

Association of CFTR gene variants with nontuberculous mycobacterial lung disease in a Korean population with a low prevalence of cystic fibrosis.

Jang MA, Kim SY, Jeong BH, Park HY, Jeon K, Kim JW, Ki CS, Koh WJ.

J Hum Genet. 2013 May;58(5):298-303. doi: 10.1038/jhg.2013.19. Epub 2013 Mar 21.

PubMed [citation]

PMID:: 23514810

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV001174878.5

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 Natera, Inc., SCV001455986.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002027436.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002988491.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 681 of the CFTR protein (p.Glu681Val). This variant is present in population databases (rs201295415, gnomAD 0.2%). This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 29173301). ClinVar contains an entry for this variant (Variation ID: 287205). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

#	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: Oct 13, 2024

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