NM_001369.3(DNAH5):c.6249G>A (p.Met2083Ile) AND Primary ciliary dyskinesia 3

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 18, 2017
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:: RCV000778755.6

Allele description [Variation Report for NM_001369.3(DNAH5):c.6249G>A (p.Met2083Ile)]

NM_001369.3(DNAH5):c.6249G>A (p.Met2083Ile)

Gene:

DNAH5:dynein axonemal heavy chain 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5p15.2

Genomic location:

Preferred name:

NM_001369.3(DNAH5):c.6249G>A (p.Met2083Ile)

HGVS:

NC_000005.10:g.13830026C>T
NG_013081.2:g.119455G>A
NM_001369.3:c.6249G>AMANE SELECT
NP_001360.1:p.Met2083Ile
NP_001360.1:p.Met2083Ile
NC_000005.9:g.13830135C>T
NM_001369.2:c.6249G>A

Note:

ClinGen staff contributed the HGVS expression for this variant.

Nucleotide change:

6249G-A

Protein change:

M2083I

Links:

OMIM: 603335.0007; dbSNP: rs753614861

NCBI 1000 Genomes Browser:

rs753614861

Molecular consequence:

NM_001369.3:c.6249G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Primary ciliary dyskinesia 3
Identifiers:: MONDO: MONDO:0012085; MedGen: C1837618; Orphanet: 244; OMIM: 608644

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000056623	OMIM	no assertion criteria provided	Pathogenic (Jan 10, 2013)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000915119	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Sep 18, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21270641, 23261302, 23891469 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000056623

OMIM

no assertion criteria provided

Pathogenic
(Jan 10, 2013)

germline

literature only

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

SCV000915119

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Likely pathogenic
(Sep 18, 2017)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Next generation massively parallel sequencing of targeted exomes to identify genetic mutations in primary ciliary dyskinesia: implications for application to clinical testing.

Berg JS, Evans JP, Leigh MW, Omran H, Bizon C, Mane K, Knowles MR, Weck KE, Zariwala MA.

Genet Med. 2011 Mar;13(3):218-29. doi: 10.1097/GIM.0b013e318203cff2.

PubMed [citation]

PMID:: 21270641
PMCID:: PMC3755008

Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia.

Knowles MR, Leigh MW, Ostrowski LE, Huang L, Carson JL, Hazucha MJ, Yin W, Berg JS, Davis SD, Dell SD, Ferkol TW, Rosenfeld M, Sagel SD, Milla CE, Olivier KN, Turner EH, Lewis AP, Bamshad MJ, Nickerson DA, Shendure J, Zariwala MA; Genetic Disorders of Mucociliary Clearance Consortium..

Am J Hum Genet. 2013 Jan 10;92(1):99-106. doi: 10.1016/j.ajhg.2012.11.003. Epub 2012 Dec 20.

PubMed [citation]

PMID:: 23261302
PMCID:: PMC3542458

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000056623.3

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

Description

For discussion of the splice site mutation in the DNAH5 gene (6249G-A) that was found in compound heterozygous state in patients with primary ciliary dyskinesia-3 (CILD3; 608644) by Knowles et al. (2013), see 603335.0006.

#	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 Illumina Laboratory Services, Illumina, SCV000915119.1

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

Description

The DNAH5 c.6249G>A (p.Met2083Ile) missense variant has been identified in a compound heterozygous state in six individuals from three families with primary ciliary dyskinesia and ciliary outer dynein arm defects demonstrated via electron microscopy (Berg et al. 2011; Knowles et al. 2013; Zariwala et al. 2013). Several of these individuals were reported to exhibit situs inversus, bronchiectasis, sinusitis and otitis media. Among these individuals, a sibling pair was shown to have inherited the variant from their healthy parent. Control data are unavailable for this variant, which is reported at a frequency of 0.000196 in the African population of the Genome Aggregation Database. RT-PCR of nasal RNA from one patient who carried a frameshift variant in trans with p.Met2083Ile demonstrated that the variant affects splicing, leading to two mutant transcripts, one showing deletion of exon 37 and the other deletion of exons 36 and 37. Both transcripts led to a premature translation termination signal (Knowles et al. 2013). Based on the collective evidence, the p.Met2083Ile variant is classified as likely pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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

Last Updated: Sep 29, 2024

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