NM_000492.4(CFTR):c.1270G>A (p.Gly424Ser) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jun 2, 2022
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:: RCV000590109.21

Allele description [Variation Report for NM_000492.4(CFTR):c.1270G>A (p.Gly424Ser)]

NM_000492.4(CFTR):c.1270G>A (p.Gly424Ser)

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.1270G>A (p.Gly424Ser)

HGVS:

NC_000007.14:g.117548701G>A
NG_016465.4:g.87918G>A
NM_000492.4:c.1270G>AMANE SELECT
NP_000483.3:p.Gly424Ser
NP_000483.3:p.Gly424Ser
LRG_663t1:c.1270G>A
LRG_663:g.87918G>A
LRG_663p1:p.Gly424Ser
NC_000007.13:g.117188755G>A
NM_000492.3:c.1270G>A
NM_000492.4:c.1270G>A

Protein change:

G424S

Links:

dbSNP: rs371107552

NCBI 1000 Genomes Browser:

rs371107552

Molecular consequence:

NM_000492.4:c.1270G>A - 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
SCV000339832	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Mar 14, 2016)	germline	clinical testing	Citation Link,
SCV000883573	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Jul 3, 2017)	germline	clinical testing	Citation Link,
SCV002759167	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 2, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000339832

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Uncertain significance
(Mar 14, 2016)

germline

clinical testing

Citation Link,

SCV000883573

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Jul 3, 2017)

germline

clinical testing

Citation Link,

SCV002759167

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jun 2, 2022)

germline

clinical testing

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	1	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Eurofins Ntd Llc (ga), SCV000339832.4

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883573.1

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

Description

The CFTR c.1270G>A; p.Gly424Ser variant (rs371107552) has been reported in two individuals from a family with rheumatoid arthritis and bronchiectasis (Puechal 2011), and reported to cause exon 9 skipping in a portion of transcripts (Pagani 2003, Aissat 2013). However, this variant occurs in a weakly conserved amino acid (Chen 2001), and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be tolerated. This variant is reported in the ClinVar database as uncertain (Variation ID: 286406), and observed in general population databases with overall allele frequencies of 0.015 percent (2/12966 alleles, Exome Variant Server), and 0.008 percent (21/272812 alleles, Genome Aggregation Database), but is considered a low confidence variant in the database due to segmental duplication. Based on the above information, the clinical significance of p.Gly424Ser is uncertain at this time. REFERENCES Link to ClinVar database for p.Gly424Ser: https://www.ncbi.nlm.nih.gov/clinvar/variation/286406/ Aissat A et al. Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. Hum Mutat. 2013 Jun;34(6):873-81. Chen JM et al. A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models. Mol Biol Evol. 2001 Sep;18(9):1771-88. Pagani F et al. Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. J Biol Chem. 2003 Jul 18;278(29):26580-8. Puechal X et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis. 2011 Apr;70(4):653-9.

#	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, SCV002759167.1

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

Description

Identified in the single heterozygous state or with a second CFTR variant, phase unknown, in an asymptomatic individual and individuals with bronchiectasis (Puchal et al., 2011; Claustres et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25735457, 12732620, 11504857, 23420618, 21131649, 29669919, 15536480, 16251901, 28603918)

#	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

Last Updated: Apr 20, 2024

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