NM_000492.4(CFTR):c.1367T>C (p.Val456Ala) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jul 22, 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:: RCV000731635.23

Allele description [Variation Report for NM_000492.4(CFTR):c.1367T>C (p.Val456Ala)]

NM_000492.4(CFTR):c.1367T>C (p.Val456Ala)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
CFTR-AS1:CFTR antisense RNA 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1367T>C (p.Val456Ala)

HGVS:

NC_000007.14:g.117548798T>C
NG_016465.4:g.88015T>C
NM_000492.4:c.1367T>CMANE SELECT
NP_000483.3:p.Val456Ala
NP_000483.3:p.Val456Ala
LRG_663t1:c.1367T>C
LRG_663:g.88015T>C
LRG_663p1:p.Val456Ala
NC_000007.13:g.117188852T>C
NM_000492.3:c.1367T>C

Protein change:

V456A

Links:

dbSNP: rs193922500

NCBI 1000 Genomes Browser:

rs193922500

Molecular consequence:

NM_000492.4:c.1367T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000859479	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Jan 31, 2018)	germline	clinical testing	Citation Link,
SCV000889282	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Dec 22, 2022)	unknown	clinical testing	PubMed (21) [See all records that cite these PMIDs] 12544470, 14998948, 17035430, 22423042, 26708955, 25651269, 26574590, 25735457, 28736296, 29216686, 30046002, 30348612, 31005549, 32906206, 22395041, 12357328, 25489051, 29805046, 31036917, 31126253, 26467025
SCV001450060	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 10, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001714234	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 13, 2019)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12357328, 25489051, 22395041, 17035430, 22423042, 28736296, 29805046, 29216686, 25741868
SCV001758624	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 22, 2024)	germline	clinical testing	Citation Link,
SCV002022516	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 13, 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	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	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

Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test.

Strom CM, Huang D, Chen C, Buller A, Peng M, Quan F, Redman J, Sun W.

Genet Med. 2003 Jan-Feb;5(1):9-14.

PubMed [citation]

PMID:: 12544470

Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis.

Danziger KL, Black LD, Keiles SB, Kammesheidt A, Turek PJ.

Hum Reprod. 2004 Mar;19(3):540-6. Epub 2004 Jan 29.

PubMed [citation]

PMID:: 14998948

See all PubMed Citations (22)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000859479.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889282.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (21)

Description

The frequency of this variant in the general population, 0.0016 (48/30028 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Cystic Fibrosis (CF) in a heterozygous state with another pathogenic variant (PMID: 12357328 (2002), 17035430 (2006), 22395041 (2012), 30348612 (2019)), and in a homozygous state (PMID: 22395041 (2012), 31126253 (2019)). It has also been reported in an asymptomatic individual in a homozygous state (PMID: 12544470 (2003)). Additionally, the variant was also reported in an individual with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 14998948 (2004)). A functional study reported this variant resulted in only 4% of protein function compared to the wild type (PMID: 29805046 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

#	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 Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450060.1

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV001714234.2

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

Description

PS3, PM2, PP3, PP5

#	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 GeneDx, SCV001758624.5

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

Description

Published functional studies demonstrate this variant to impact function similar to other known CF-causing variants (PMID: 29805046); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29805046, 29216686, 25489051, 28502372, 22395041, 31126253, 31005549, 14998948, 12544470, 24149827, 12357328, 31036917, 34842611, 32366966, 32734384, 22423042, 35652053, 35857025, Conti 2023[Review], 35761057, 34782259, 37313453, 17035430, 38515211)

#	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 Revvity Omics, Revvity, SCV002022516.3

#	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

Last Updated: Oct 13, 2024

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