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

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000214042.20

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]

Observations:

Condition(s)

Name:: Primary ciliary dyskinesia
Synonyms:: Ciliary dyskinesia
Identifiers:: MONDO: MONDO:0016575; MedGen: C0008780; OMIM: PS244400; Human Phenotype Ontology: HP:0012265

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000271213	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Feb 24, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23261302, 24033266
SCV000287091	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 2127064, 2389146, 23261302, 17576681, 9536098, 28492532
SCV001431585	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 8, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25741868, 23261302, 21270641
SCV002106423	Yale Center for Mendelian Genomics, Yale University - Yale Center for Mendelian Genomics	no assertion criteria provided	Likely pathogenic (Aug 1, 2018)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002656417	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 5, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21270641, 23261302, 23891469 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	1	not provided	not provided	not provided	literature only, clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

[Study of anti-ischemic action of carnitine chloride and its effects on the effectiveness of antianginal agents].

Tishkin VS, Dunaev VV, Kryzhanovskiĭ SA, Riabinin VA, Favoritov VN, Danilovich MI, Kacharava VG.

Kardiologiia. 1990 Oct;30(10):89-91. Russian.

PubMed [citation]

PMID:: 2127064

See all PubMed Citations (11)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271213.2

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

Description

The p.Met2083Ile variant in DNAH5 has been reported in trans with a second DNAH5 variant (Met754Ilefs) in 1 individual with primary ciliary dyskinesia. Both var iants were present in 1 affected sibling (Knowles 2013). This variant has been identified in 1/66400 European chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs753614861). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance , pathogenic variants may be present at a low frequency in the general populatio n. This variant affects the last base of the exon, which is part of the 5? splic e region, and has been shown to affect splicing (Knowles 2013). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Met2083Ile variant is likely pathogenic in an autosomal recessive fashi on

#	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		1	not provided	1	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000287091.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2083 of the DNAH5 protein (p.Met2083Ile). This variant also falls at the last nucleotide of exon 37, which is part of the consensus splice site for this exon. This variant is present in population databases (rs753614861, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 2127064, 2389146, 23261302). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228251). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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

From UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill, SCV001431585.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing (GTR000576399.1)	PubMed (3)

#	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	(GTR000576399.1)	1	not provided	1	not provided

From Yale Center for Mendelian Genomics, Yale University - Yale Center for Mendelian Genomics, SCV002106423.1

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

From Ambry Genetics, SCV002656417.2

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

Description

The c.6249G>A pathogenic mutation (also known as p.M2083I), located in coding exon 37 of the DNAH5 gene, results from a G to A substitution at nucleotide position 6249. The methionine at codon 2083 is replaced by isoleucine, an amino acid with highly similar properties. This change occurs in the last base pair of coding exon 37, which makes it likely to have some effect on normal mRNA splicing. This variant was described in two siblings with outer dynein arm defects detected by electron microscopy, and a frameshift alteration confirmed in trans. Studies demonstrated that this alteration leads to abnormal splicing and premature protein truncation (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106). In addition, this mutation was reported in two individuals with primary ciliary dyskinesia, both with situs inversus, outer dynein arm defects on electron microscopy, and a second DNAH5 alteration (Berg JS et al. Genet. Med., 2011 Mar;13:218-29; Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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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