NM_000492.4(CFTR):c.273G>C (p.Gly91=) AND Cystic fibrosis

Clinical significance:Likely pathogenic (Last evaluated: May 17, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000587955.3

Allele description [Variation Report for NM_000492.4(CFTR):c.273G>C (p.Gly91=)]

NM_000492.4(CFTR):c.273G>C (p.Gly91=)

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.273G>C (p.Gly91=)
HGVS:
  • NC_000007.14:g.117509142G>C
  • NG_016465.4:g.48359G>C
  • NG_062452.1:g.780G>C
  • NM_000492.4:c.273G>CMANE SELECT
  • NP_000483.3:p.Gly91=
  • NP_000483.3:p.Gly91=
  • LRG_663t1:c.273G>C
  • LRG_663:g.48359G>C
  • LRG_663p1:p.Gly91=
  • NC_000007.13:g.117149196G>C
  • NM_000492.3:c.273G>C
Links:
dbSNP: rs773739166
NCBI 1000 Genomes Browser:
rs773739166
Molecular consequence:
  • NM_000492.4:c.273G>C - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:
Cystic fibrosis (CF)
Synonyms:
Mucoviscidosis
Identifiers:
MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000696895Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Jun 1, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001385257Invitaecriteria provided, single submitter
Likely pathogenic
(May 17, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Extensive molecular analysis suggested the strong genetic heterogeneity of idiopathic chronic pancreatitis.

Sofia VM, Da Sacco L, Surace C, Tomaiuolo AC, Genovese S, Grotta S, Gnazzo M, Ciocca L, Petrocchi S, Alghisi F, Montemitro E, Martemucci L, Elce A, Lucidi V, Castaldo G, Angioni A.

Mol Med. 2016 Sep;22:300-309. doi: 10.2119/molmed.2016.00010. Epub 2016 May 26.

PubMed [citation]
PMID:
27264265
PMCID:
PMC5023519

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696895.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: The CFTR c.273G>C (p.Gly91Gly) variant involves the alteration of the last nucleotide of exon 3, resulting in a synonymous change. One in silico tool predicts damaging outcome for this variant. 4/5 splice prediction tools predict that this variant significantly abolishe or weaken the 3' splicing donor site. This prediction has been confirmed by cDNA analysis in a 9-year-old CF patient (Tomaiuolo_2015), who had positive sweat chloride test and pancreatitis. The variant of interest is absent in 120908 control chromosomes from ExAC. One reputable database has classified it as disease-causing. Taken together, this variant is classified as a Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001385257.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change affects codon 91 of the CFTR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CFTR protein. This variant also falls at the last nucleotide of exon 3 of the CFTR coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with CFTR-related conditions (PMID: 25636364, 27264265). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 495909). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 25636364). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

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