NM_012472.6(DNAAF11):c.299T>C (p.Ile100Thr) AND Ciliary dyskinesia, primary, 19

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Feb 10, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000650327.5

Allele description [Variation Report for NM_012472.6(DNAAF11):c.299T>C (p.Ile100Thr)]

NM_012472.6(DNAAF11):c.299T>C (p.Ile100Thr)

Gene:
DNAAF11:dynein axonemal assembly factor 11 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
8q24.22
Genomic location:
Preferred name:
NM_012472.6(DNAAF11):c.299T>C (p.Ile100Thr)
HGVS:
  • NC_000008.11:g.132638065A>G
  • NG_033068.1:g.42553T>C
  • NM_001321961.2:c.299T>C
  • NM_001321962.2:c.53T>C
  • NM_001321963.2:c.-62T>C
  • NM_001321964.2:c.-62T>C
  • NM_001321965.2:c.-62T>C
  • NM_001321966.2:c.-62T>C
  • NM_012472.6:c.299T>CMANE SELECT
  • NP_001308890.1:p.Ile100Thr
  • NP_001308891.1:p.Ile18Thr
  • NP_036604.2:p.Ile100Thr
  • NC_000008.10:g.133650311A>G
  • NM_012472.4:c.299T>C
  • NR_073525.3:n.351T>C
  • NR_135905.2:n.664T>C
  • NR_135906.2:n.105T>C
  • NR_135907.2:n.351T>C
  • NR_135908.2:n.105T>C
  • NR_135909.2:n.561T>C
  • NR_135910.2:n.911T>C
  • NR_135911.2:n.1031T>C
  • NR_135912.2:n.1590T>C
  • NR_135913.2:n.1277T>C
Protein change:
I100T
Links:
dbSNP: rs139008774
NCBI 1000 Genomes Browser:
rs139008774
Molecular consequence:
  • NM_001321963.2:c.-62T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001321964.2:c.-62T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001321965.2:c.-62T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001321966.2:c.-62T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001321961.2:c.299T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001321962.2:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012472.6:c.299T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_073525.3:n.351T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_135905.2:n.664T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_135906.2:n.105T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_135907.2:n.351T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_135908.2:n.105T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_135909.2:n.561T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_135910.2:n.911T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_135911.2:n.1031T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_135912.2:n.1590T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_135913.2:n.1277T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Ciliary dyskinesia, primary, 19 (CILD19)
Synonyms:
CILIARY DYSKINESIA, PRIMARY, 19, WITH OR WITHOUT SITUS INVERSUS
Identifiers:
MONDO: MONDO:0013979; MedGen: C3543826; Orphanet: 244; OMIM: 614935

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000772170Invitaecriteria provided, single submitter
Pathogenic
(Feb 10, 2020)
germlineclinical testing

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

SCV001321562Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jan 12, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

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

Citations

PubMed

Diagnosis of Primary Ciliary Dyskinesia by a Targeted Next-Generation Sequencing Panel: Molecular and Clinical Findings in Italian Patients.

Boaretto F, Snijders D, Salvoro C, Spalletta A, Mostacciuolo ML, Collura M, Cazzato S, Girosi D, Silvestri M, Rossi GA, Barbato A, Vazza G.

J Mol Diagn. 2016 Nov;18(6):912-922. doi: 10.1016/j.jmoldx.2016.07.002. Epub 2016 Sep 13.

PubMed [citation]
PMID:
27637300

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000772170.4

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

Description

This sequence change replaces isoleucine with threonine at codon 100 of the LRRC6 protein (p.Ile100Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs139008774, ExAC 0.02%). This variant has been observed in individual(s) with clinical features of primary ciliary dyskinesia (PMID: 27637300, Invitae). 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: 540329). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.

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

From Illumina Clinical Services Laboratory,Illumina, SCV001321562.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

Last Updated: May 10, 2021

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