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

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 21, 2020
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:: RCV000176372.17

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:: Hereditary pancreatitis (PCTT)
Synonyms:: Hereditary chronic pancreatitis
Identifiers:: MONDO: MONDO:0008185; MedGen: C0238339; Orphanet: 676; OMIM: 167800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000602988	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (May 15, 2018)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 23891399, 23974870, 10386624, 8343799, 7532150, 23951356, 21520337, 9950364, 1545465 Citation Link,
SCV002529719	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely benign (Dec 21, 2020)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000602988

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(May 15, 2018)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV002529719

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely benign
(Dec 21, 2020)

germline

curation

Citation Link

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	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

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

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.

Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR.

Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25.

PubMed [citation]

PMID:: 23974870
PMCID:: PMC3874936

See all PubMed Citations (9)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000602988.2

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

Description

The CFTR c.3808G>A, p.Asp1270Asn variant (rs11971167) has been reported in patients diagnosed with congenital bilateral absence of vas deferens (CBAVD), in trans with p.Phe508del (Anguiano 1992, Oates 1993), but is more commonly found in a complex allele (with p.Arg74Trp and p.Val201Met) in patients with CBAVD and pancreatitis (Bareil 2007, Casals 1995, Masson 2013, Steiner 2011). In individuals where the p.Asp1270Asn alone was reported in trans with p.Phe508del, they had normal or slightly elevated sweat chloride levels (Anguiano 1992, Padoa 1999). Functional characterization of the p.Asp1270Asn variant indicates reduced overall mRNA and protein expression (van Goor 2014), reduced chloride conductance (Sosnay 2013, van Goor 2014) and altered response patterns (Fanen 1999). However, protein maturation and glycosylation is comparable to wildtype (Fanen 1999, Sosnay 2013, van Goor 2014). This variant is found in the general population with an overall allele frequency of 0.1% (315/276666 alleles, including 3 homozygotes) in the Genome Aggregation Database. The aspartate at residue 1270 is highly conserved, and computational algorithms ( PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as very mildly pathogenic.

#	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 Sema4, Sema4, SCV002529719.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	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

Last Updated: Oct 26, 2024

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