NM_001256715.2(DNAAF3):c.182T>C (p.Leu61Pro) AND Primary ciliary dyskinesia 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 5, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000024243.12

Allele description [Variation Report for NM_001256715.2(DNAAF3):c.182T>C (p.Leu61Pro)]

NM_001256715.2(DNAAF3):c.182T>C (p.Leu61Pro)

Genes:

DNAAF3-AS1:DNAAF3 antisense RNA 1 [Gene - HGNC]
DNAAF3:dynein axonemal assembly factor 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.42

Genomic location:

Preferred name:

NM_001256715.2(DNAAF3):c.182T>C (p.Leu61Pro)

HGVS:

NC_000019.10:g.55165904A>G
NG_032759.1:g.5819T>C
NM_001256714.1:c.386T>C
NM_001256715.2:c.182T>CMANE SELECT
NM_001256716.2:c.-57T>C
NM_178837.4:c.323T>C
NP_001243643.1:p.Leu129Pro
NP_001243644.1:p.Leu61Pro
NP_849159.2:p.Leu108Pro
NC_000019.9:g.55677272A>G
NM_001256715.2:c.182T>C

Protein change:

L108P; LEU108PRO

Links:

OMIM: 614566.0001; dbSNP: rs387907151

NCBI 1000 Genomes Browser:

rs387907151

Molecular consequence:

NM_001256716.2:c.-57T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001256714.1:c.386T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001256715.2:c.182T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_178837.4:c.323T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Primary ciliary dyskinesia 2
Synonyms:: CILIARY DYSKINESIA, PRIMARY, 2, WITH OR WITHOUT SITUS INVERSUS
Identifiers:: MONDO: MONDO:0011718; MedGen: C1847554; Orphanet: 244; OMIM: 606763

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000045534	OMIM	no assertion criteria provided	Pathogenic (Mar 4, 2012)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10745040, 22387996
SCV005201010	Genomics, Clalit Research Institute, Clalit Health Care	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 5, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000045534

OMIM

no assertion criteria provided

Pathogenic
(Mar 4, 2012)

germline

literature only

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

SCV005201010

Genomics, Clalit Research Institute, Clalit Health Care

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 5, 2024)

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Bedouin	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A locus for primary ciliary dyskinesia maps to chromosome 19q.

Meeks M, Walne A, Spiden S, Simpson H, Mussaffi-Georgy H, Hamam HD, Fehaid EL, Cheehab M, Al-Dabbagh M, Polak-Charcon S, Blau H, O'Rawe A, Mitchison HM, Gardiner RM, Chung E.

J Med Genet. 2000 Apr;37(4):241-4.

PubMed [citation]

PMID:: 10745040
PMCID:: PMC1734555

Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia.

Mitchison HM, Schmidts M, Loges NT, Freshour J, Dritsoula A, Hirst RA, O'Callaghan C, Blau H, Al Dabbagh M, Olbrich H, Beales PL, Yagi T, Mussaffi H, Chung EM, Omran H, Mitchell DR.

Nat Genet. 2012 Mar 4;44(4):381-9, S1-2. doi: 10.1038/ng.1106.

PubMed [citation]

PMID:: 22387996
PMCID:: PMC3315610

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000045534.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 4 affected sibs of a consanguineous Israeli family with primary ciliary dyskinesia-2 (CILD2; 606763) originally ascertained by Meeks et al. (2000), Mitchison et al. (2012) identified a homozygous 323T-C transition in exon 3 of the DNAAF3 gene, resulting in a leu108-to-pro (L108P) substitution at a highly conserved residue. The mutation was not found in 148 controls. The patients had sinusitis, bronchiectasis, and severe pulmonary disease. Three had otitis media, 1 had infertility, and 1 had situs inversus. Immunohistochemical and electron microscopic studies showed ciliary defects of the inner and outer dynein arms, with loss of the outer dynein components DNAH5 (603335), DNAH9 (603330), and DNAH12 (603340), as well as loss of the inner dynein component DNALI1 (602315). The cilia were demonstrated to be immotile.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomics, Clalit Research Institute, Clalit Health Care, SCV005201010.1

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

Description

Inheritance: The variant was identified in the Homozygous state in the sample. Frequency: The variant is absent from the gnomAD reference population dataset. Allelic data: This variant was previously reported in a homozgote state (PMID:22387996). Frequency among cases: This variant was identified in homozygous state in several PCD individuals from the Bedouin subpopulation. Segregation: The variant is segregate with disease in multiple affected family members in a gene definitively known to cause disease (PMID:22387996). Prediction tools: REVEL predicts an uncertain impact on the gene or gene product (score 0.42). Clinical evidence: This variant has previously been described in ClinVar (VCV31532) with the following classifications: P (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		1	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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