NM_000492.4(CFTR):c.358G>A (p.Ala120Thr) AND not provided

Germline classification:: Uncertain significance (7 submissions)
Last evaluated:: Jan 3, 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:: RCV000587814.35

Allele description [Variation Report for NM_000492.4(CFTR):c.358G>A (p.Ala120Thr)]

NM_000492.4(CFTR):c.358G>A (p.Ala120Thr)

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.358G>A (p.Ala120Thr)

HGVS:

NC_000007.14:g.117530983G>A
NG_016465.4:g.70200G>A
NM_000492.4:c.358G>AMANE SELECT
NP_000483.3:p.Ala120Thr
NP_000483.3:p.Ala120Thr
LRG_663t1:c.358G>A
LRG_663:g.70200G>A
LRG_663p1:p.Ala120Thr
NC_000007.13:g.117171037G>A
NM_000492.3:c.358G>A
P13569:p.Ala120Thr

Protein change:

A120T

Links:

UniProtKB: P13569#VAR_000125; dbSNP: rs201958172

NCBI 1000 Genomes Browser:

rs201958172

Molecular consequence:

NM_000492.4:c.358G>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
SCV001371084	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Dec 1, 2023)	germline	clinical testing	Citation Link,
SCV001983132	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 3, 2024)	germline	clinical testing	Citation Link,
SCV003799538	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Jul 22, 2022)	germline	clinical testing	Citation Link,
SCV003831655	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004221690	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jan 6, 2023)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 31916691, 31990467, 31488014, 28830496, 22427236, 21520337, 15727251, 12752573, 11883825, 11354633, 10439967, 9439669, 9272157, 7513293, 23951356, 7517264, 15537723, 21198395, 17489851, 26467025
SCV005195609	Breakthrough Genomics, Breakthrough Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV005197449	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 14, 2022)	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	2	not provided	not provided	not provided	not provided	clinical testing, not provided
not provided	germline	unknown	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

Phenotype of children with inconclusive cystic fibrosis diagnosis after newborn screening.

Munck A, Bourmaud A, Bellon G, Picq P, Farrell PM; DPAM Study Group..

Pediatr Pulmonol. 2020 Apr;55(4):918-928. doi: 10.1002/ppul.24634. Epub 2020 Jan 9.

PubMed [citation]

PMID:: 31916691

Two years of newborn screening for cystic fibrosis in Turkey: Çukurova experience.

Şaşihüseyinoğlu AŞ, Altıntaş DU, Bişgin A, Doğruel D, Yılmaz M, Serbes M.

Turk J Pediatr. 2019;61(4):505-512. doi: 10.24953/turkjped.2019.04.006.

PubMed [citation]

PMID:: 31990467

See all PubMed Citations (21)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001371084.24

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

Description

CFTR: PM1, PM2, PM3:Supporting

#	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		2	not provided	not provided	not provided

From GeneDx, SCV001983132.4

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

Description

In silico analysis supports that this missense variant does not alter protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 9272157, 15537723, 11354633, 23951356, 27449771, 19318035, 21520337, 22427236, 9439669, 12752573, 7517264, 21198395, 7513293, 15727251, 23523379, 7532150, 17489851, 11883825, 34426522, 31488014, 33572515, 34405919, 33988008, 34996830, 31990467, 31916691, 34525262, 37313453, 35769956, 18687795, 10439967, 28830496)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV003799538.2

#	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.358G>A; p.Ala120Thr variant (rs201958172) has been observed in individuals with cystic fibrosis (CFTR2 database, Chillon 1994, Jalalirad 2004, Padoan 2002, Radivojevic 2004, Sasihuseyinoglu 2019), pancreatitis (Masson 2013), and congenital bilateral absence of vas deferens (Dork 1997). In several individuals with cystic fibrosis, a second pathogenic variant was also identified (Padoan 2002; Sasihuseyinoglu 2019), but a second variant was not reported in many patients carrying p.Ala120Thr. The p.Ala120Thr variant is reported in ClinVar (Variation ID: 53774). The CFTR2 database describes p.Ala120Thr as having varying clinical consequences and those with cystic fibrosis are likely to be pancreatic sufficient (CFTR2 database). This variant is found in the general population with an overall allele frequency of 0.01% (39/282308 alleles) in the Genome Aggregation Database. The alanine at codon 120 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.787). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: CFTR2 database: https://cftr2.org/ Chillon M et al. Analysis of the CFTR gene confirms the high genetic heterogeneity of the Spanish population: 43 mutations account for only 78% of CF chromosomes. Hum Genet. 1994 Apr;93(4):447-51. PMID: 7513293. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 Sep;100(3-4):365-77. PMID: 9272157. Jalalirad M et al. First study of CF mutations in the CFTR gene of Iranian patients: detection of DeltaF508, G542X, W1282X, A120T, R117H, and R347H mutations. J Trop Pediatr. 2004 Dec;50(6):359-61. PMID: 15537723. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 Aug 8;8(8):e73522. PMID: 23951356. Padoan R et al. Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis. Acta Paediatr. 2002;91(1):82-7. PMID: 11883825. Radivojevic D et al. Spectrum of cystic fibrosis mutations in Serbia and Montenegro and strategy for prenatal diagnosis. Genet Test. 2004 Fall;8(3):276-80. PMID: 15727251. Sasihuseyinoglu AS et al. Two years of newborn screening for cystic fibrosis in Turkey: Çukurova experience. Turk J Pediatr. 2019;61(4):505-512. PMID: 31990467.

#	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 Revvity Omics, Revvity, SCV003831655.2

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004221690.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

The frequency of this variant in the general population, 0.00043 (13/30578 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported with varying clinical consequences in individuals with cystic fibrosis (PMIDs: 31990467 (2019), 15537723 (2004), 15727251 (2004), 12752573 (2003), 10439967 (1999), 7517264 (1994)), and individuals without cystic fibrosis (PMIDs: 22427236 (2013), 21520337 (2011), 17489851 (2007), 11883825 (2002)). Additionally, the variant has been reported in individuals with pancreatic insufficiency (PMID: 28830496 (2017)), idiopathic chronic pancreatitis (PMID: 23951356 (2013), and congenital absence of the vas deferens (PMID: 9272157 (1997)). 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.

#	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 Breakthrough Genomics, Breakthrough Genomics, SCV005195609.1

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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005197449.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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