NM_000492.4(CFTR):c.2816A>G (p.His939Arg) AND Cystic fibrosis

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 10, 2024
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:: RCV002433535.3

Allele description [Variation Report for NM_000492.4(CFTR):c.2816A>G (p.His939Arg)]

NM_000492.4(CFTR):c.2816A>G (p.His939Arg)

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.2816A>G (p.His939Arg)

HGVS:

NC_000007.14:g.117603690A>G
NG_016465.4:g.142907A>G
NM_000492.4:c.2816A>GMANE SELECT
NP_000483.3:p.His939Arg
NP_000483.3:p.His939Arg
LRG_663t1:c.2816A>G
LRG_663:g.142907A>G
LRG_663p1:p.His939Arg
NC_000007.13:g.117243744A>G
NM_000492.3:c.2816A>G

Protein change:

H939R

Links:

dbSNP: rs397508440

NCBI 1000 Genomes Browser:

rs397508440

Molecular consequence:

NM_000492.4:c.2816A>G - 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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Homo sapiens cDNA clone IMAGE:40012378, containing frame-shift errors
Homo sapiens cDNA clone IMAGE:40012378, containing frame-shift errors
gi|73695302|gb|BC103497.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001478574	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 10, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10923036, 21931512, 12186867, 26098992, 26911355, 33085659, 28475858, 25898134, 29371133 Citation Link,
SCV002749480	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 11, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10923036, 21931512, 33085659 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001478574

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 10, 2024)

germline

clinical testing

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

Citation Link,

SCV002749480

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 11, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

Citations

PubMed

Cooperativity and flexibility of cystic fibrosis transmembrane conductance regulator transmembrane segments participate in membrane localization of a charged residue.

Carveth K, Buck T, Anthony V, Skach WR.

J Biol Chem. 2002 Oct 18;277(42):39507-14. Epub 2002 Aug 18.

PubMed [citation]

PMID:: 12186867

Utility of a very high IRT/No mutation referral category in cystic fibrosis newborn screening.

Kay DM, Langfelder-Schwind E, DeCelie-Germana J, Sharp JK, Maloney B, Tavakoli NP, Saavedra-Matiz CA, Krein LM, Caggana M, Kier C; New York State Cystic Fibrosis Newborn Screening Consortium..

Pediatr Pulmonol. 2015 Aug;50(8):771-80. doi: 10.1002/ppul.23222. Epub 2015 Jun 22.

PubMed [citation]

PMID:: 26098992

See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001478574.2

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

Description

Variant summary: CFTR c.2816A>G (p.His939Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, several computational tools predict a significant impact on normal splicing: three predict the variant creates a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in the activation of a cryptic 5' donor site and leading to a frameshift (e.g., Lee_2017). The variant was absent in 251404 control chromosomes (gnomAD). c.2816A>G has been reported in the literature as an isolated variant in individuals affected with Cystic Fibrosis (at least two ascertainments; e.g., Claustres_2000, Trimble_2018), CBAVD (at least one ascertainment; e.g., Claustres_2000), newborns with very high immunoreactive trypsinogen levels (at least one ascertainment; e.g., Kay_2015). It has also been reported as a complex allele in cis with p.H949L and another disease causing CF variant in trans (i.e., compound heterozygous genotype) in patients with CF (at least four ascertainments) and CFTR-RD (at-least one ascertainment) (e.g., Polizzi_2011, Diana_2016, Paganin_2015). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g., Carveth_2002, Lee_2017, Joynt_2020). Two of these publications report that both transcripts that were improperly spliced due to the variant as well as transcripts with the variant and no introns resulted in loss of mature CFTR protein (Lee_2017, Joynt_2020). The following publications have been ascertained in the context of this evaluation (PMID: 12186867, 10923036, 26911355, 33085659, 26098992, 28475858, 25898134, 21931512, 29371133). ClinVar contains an entry for this variant (Variation ID: 53573). Based on the evidence outlined above, the variant was classified as likely 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, SCV002749480.2

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

Description

The p.H939R pathogenic mutation (also known as c.2816A>G), located in coding exon 17 of the CFTR gene, results from an A to G substitution at nucleotide position 2816. The histidine at codon 939 is replaced by arginine, an amino acid with highly similar properties. This variant was also reported as part of a complex allele [H939R;H949L] in five individuals from an Italian CF cohort, all of whom had another CFTR variant identified as in trans; four of the cases had classic CF phenotypes, and one had CFTR-related disease (Polizzi A et al. Genet. Mol. Biol., 2011 Jul;34:416-20). A minigene assay with this alteration showed a 97-nucleotide deletion due to activation of a cryptic donor site, leading to out-of-frame transcript. In addition, p.H939R resulted in misfolded protein when translated (Lee M et al. Am J Hum Genet, 2017 May;100:751-765). 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

Last Updated: Oct 13, 2024

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