NM_000492.4(CFTR):c.1731C>T (p.Tyr577=) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Feb 2, 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:: RCV001508586.22

Allele description [Variation Report for NM_000492.4(CFTR):c.1731C>T (p.Tyr577=)]

NM_000492.4(CFTR):c.1731C>T (p.Tyr577=)

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.1731C>T (p.Tyr577=)

HGVS:

NC_000007.14:g.117590404C>T
NG_016465.4:g.129621C>T
NM_000492.4:c.1731C>TMANE SELECT
NP_000483.3:p.Tyr577=
NP_000483.3:p.Tyr577=
LRG_663t1:c.1731C>T
LRG_663:g.129621C>T
LRG_663p1:p.Tyr577=
NC_000007.13:g.117230458C>T
NM_000492.3:c.1731C>T
p.Tyr577=

Links:

dbSNP: rs55928397

NCBI 1000 Genomes Browser:

rs55928397

Molecular consequence:

NM_000492.4:c.1731C>T - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV001477819	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Dec 3, 2020)	germline	clinical testing	Citation Link,
SCV001714835	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 2, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003831646	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004221666	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Oct 11, 2022)	unknown	clinical testing	PubMed (13) [See all records that cite these PMIDs] 26761715, 25735457, 25492507, 23890012, 22591852, 18687795, 12719375, 17172597, 15840711, 15463919, 22362925, 32935393, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	3	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools.

Soukarieh O, Gaildrat P, Hamieh M, Drouet A, Baert-Desurmont S, Frébourg T, Tosi M, Martins A.

PLoS Genet. 2016 Jan;12(1):e1005756. doi: 10.1371/journal.pgen.1005756. Erratum in: PLoS Genet. 2016 Apr 06;12(4):e1005971. doi: 10.1371/journal.pgen.1005971.

PubMed [citation]

PMID:: 26761715
PMCID:: PMC4711968

See all PubMed Citations (14)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001477819.2

#	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.1731C>T; p.Tyr577Tyr variant (rs55928397), is reported in the literature in an individual affected with cystic fibrosis (SickKids CFTR database). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (46/128572 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 35832). This is a synonymous variant in a weakly conserved nucleotide; however, it occurs in an exonic splicing enhancer element and minigene assays indicate it may lead to increased skipping of exon 12 (Amaral 2004, Fernandez Alanis 2012, Pagani 2005), although this has not been demonstrated in patient cells with this variant. Given the lack of clinical and functional data, the significance of the c.1731C>T variant is uncertain at this time. References: SickKids CFTR database entry for p.Tyr577Tyr: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=755 Amaral MD et al. Quantitative methods for the analysis of CFTR transcripts/splicing variants. J Cyst Fibros. 2004 Aug;3 Suppl 2:17-23. Fernandez Alanis et al. An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Hum Mol Genet. 2012 Jun 1;21(11):2389-98. Pagani F et al. Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution. Proc Natl Acad Sci U S A. 2005 May 3;102(18):6368-72.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV001714835.3

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

Description

PM2_supporting, PS3

#	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		3	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003831646.2

#	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, SCV004221666.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The frequency of this variant in the general population, 0.00036 (46/128572 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with idiopathic chronic pancreatitis (PMIDs: 18687795 (2008) and 25492507 (2015)). Functional studies predict exon 12 skipping and did not show any detectable protein (PMIDs: 15463919 (2004), 22362925 (2012), 22591852 (2012), and 32935393 (2020)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CFTR mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.

#	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

Last Updated: Oct 26, 2024

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