NM_000492.4(CFTR):c.3808G>A (p.Asp1270Asn) AND Cystic fibrosis

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Jun 3, 2024
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:: RCV000046985.31

Allele description [Variation Report for NM_000492.4(CFTR):c.3808G>A (p.Asp1270Asn)]

NM_000492.4(CFTR):c.3808G>A (p.Asp1270Asn)

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.3808G>A (p.Asp1270Asn)

HGVS:

NC_000007.14:g.117642528G>A
NG_016465.4:g.181745G>A
NM_000492.4:c.3808G>AMANE SELECT
NP_000483.3:p.Asp1270Asn
NP_000483.3:p.Asp1270Asn
LRG_663t1:c.3808G>A
LRG_663:g.181745G>A
LRG_663p1:p.Asp1270Asn
NC_000007.13:g.117282582G>A
NM_000492.3:c.3808G>A
P13569:p.Asp1270Asn

Protein change:

D1270N; ASP1270ASN

Links:

Genetic Testing Registry (GTR): GTR000257096; UniProtKB: P13569#VAR_000260; OMIM: 602421.0060; dbSNP: rs11971167

NCBI 1000 Genomes Browser:

rs11971167

Molecular consequence:

NM_000492.4:c.3808G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000074998	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000795824	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Nov 19, 2017)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 23891399, 27738188, 23974870, 10762539, 20880762, 12172395, 10386624, 15371903, 15287992 Citation Link,
SCV001137497	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001182780	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 3, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18703181, 21520337, 23951356 Citation Link,
SCV001430641	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 11, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001481661	Baylor Genetics - CSER-TexasKidsCanSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 20, 2020)	unknown	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	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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function.

Van Goor F, Yu H, Burton B, Hoffman BJ.

J Cyst Fibros. 2014 Jan;13(1):29-36. doi: 10.1016/j.jcf.2013.06.008. Epub 2013 Jul 23.

PubMed [citation]

PMID:: 23891399

See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000074998.11

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

From Counsyl, SCV000795824.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	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, SCV001137497.1

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

From Ambry Genetics, SCV001182780.6

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

Description

The p.D1270N variant (also known as c.3808G>A) is located in coding exon 23 of the CFTR gene in the NDB2 domain. This alteration results from a G to A substitution at nucleotide position 3808. The aspartic acid at codon 1270 is replaced by asparagine, an amino acid with some highly similar properties. This variant is typically found as part of the complex allele p.[R74W; V201M; D1270N] (de Prada Merino A et al. J. Cyst. Fibros. 2010; 9(6):447-9). This complex allele has been identified in the homozygous state and in trans with a pathogenic mutation in CFTR in individuals with CBAVD (Steiner B et al. Hum. Mutat. 2011; 32(8):912-20). This alteration has also been identified in individuals with pancreatitis (Masson E et al. PLoS One, 2013 Aug;8:e73522). One functional study found that this alteration resulted in normal protein processing, but it had a lower rate of cAMP-responsive anion conductance than the wild-type allele, similar to that of the p.R117H mutation (Fanen P et al. FEBS Lett. 1999;452(3):371-374). However, this alteration has also been described in trans with deleterious mutations in CFTR in healthy individuals, though CBAVD was not ruled out (Claustres M et al. BMC Med Genet. 2004;5:19; Brugnon F et al. Fertil Steril. 2008;90(5):2004.e23-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of evidence, this variant is not likely to cause classic CF; however, its role in CFTR-related conditions is unclear.

#	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, SCV001430641.1

#	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

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV001481661.2

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	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

Last Updated: Oct 26, 2024

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