NM_000492.4(CFTR):c.2846A>T (p.His949Leu) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Jan 8, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001290523.1

Allele description [Variation Report for NM_000492.4(CFTR):c.2846A>T (p.His949Leu)]

NM_000492.4(CFTR):c.2846A>T (p.His949Leu)

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.2846A>T (p.His949Leu)
HGVS:
  • NC_000007.14:g.117603720A>T
  • NG_016465.4:g.142937A>T
  • NM_000492.3:c.2846A>T
  • NM_000492.4:c.2846A>TMANE SELECT
  • NP_000483.3:p.His949Leu
  • NP_000483.3:p.His949Leu
  • LRG_663t1:c.2846A>T
  • LRG_663:g.142937A>T
  • LRG_663p1:p.His949Leu
  • NC_000007.13:g.117243774A>T
Protein change:
H949L
Links:
dbSNP: rs397508444
NCBI 1000 Genomes Browser:
rs397508444
Molecular consequence:
  • NM_000492.3:c.2846A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000492.4:c.2846A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001478575Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Jan 8, 2021)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples.

McGinniss MJ, Chen C, Redman JB, Buller A, Quan F, Peng M, Giusti R, Hantash FM, Huang D, Sun W, Strom CM.

Hum Genet. 2005 Dec;118(3-4):331-8. Epub 2005 Sep 28.

PubMed [citation]
PMID:
16189704

Genotype-phenotype correlation in cystic fibrosis patients bearing [H939R;H949L] allele.

Polizzi A, Tesse R, Santostasi T, Diana A, Manca A, Logrillo VP, Cazzato MD, Pantaleo MG, Armenio L.

Genet Mol Biol. 2011 Jul;34(3):416-20. doi: 10.1590/S1415-47572011000300008. Epub 2011 Jul 1.

PubMed [citation]
PMID:
21931512
PMCID:
PMC3168180

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001478575.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: CFTR c.2846A>T (p.His949Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2846A>T has been reported in the literature in at-least one individual with atypical CF and equivocal sweat chloride levels (example, McGinniss_2005). It has also been reported as a complex allele in cis with p.H949L and another disease causing CF variant in trans (i.e., compound heterozygous genotype) in patients with CF (at-least four ascertainments) and CFTR-RD (at-least one ascertainment) (example, Polizzi_2011, Diana_2016, Paganin_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis in isolation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. One submitter has cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Nov 27, 2021

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