NM_001369.3(DNAH5):c.10616G>A (p.Arg3539His) AND Primary ciliary dyskinesia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 19, 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:: RCV000198195.13

Allele description [Variation Report for NM_001369.3(DNAH5):c.10616G>A (p.Arg3539His)]

NM_001369.3(DNAH5):c.10616G>A (p.Arg3539His)

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.10616G>A (p.Arg3539His)

HGVS:

NC_000005.10:g.13753489C>T
NG_013081.2:g.195992G>A
NM_001369.3:c.10616G>AMANE SELECT
NP_001360.1:p.Arg3539His
NP_001360.1:p.Arg3539His
NC_000005.9:g.13753598C>T
NM_001369.2:c.10616G>A

Protein change:

R3539H

Links:

dbSNP: rs769458738

NCBI 1000 Genomes Browser:

rs769458738

Molecular consequence:

NM_001369.3:c.10616G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000254739	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22416021, 22499950, 24498942, 26373788, 28492532
SCV002714541	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 20, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 22416021, 22499950, 23891469, 24498942, 26228299, 26373788, 32111882, 33715250 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000254739

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 19, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002714541

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 20, 2023)

germline

clinical testing

PubMed (8)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Effectiveness of sequencing selected exons of DNAH5 and DNAI1 in diagnosis of primary ciliary dyskinesia.

Djakow J, Svobodová T, Hrach K, Uhlík J, Cinek O, Pohunek P.

Pediatr Pulmonol. 2012 Sep;47(9):864-75. doi: 10.1002/ppul.22520. Epub 2012 Mar 13.

PubMed [citation]

PMID:: 22416021

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000254739.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3539 of the DNAH5 protein (p.Arg3539His). This variant is present in population databases (rs769458738, gnomAD 0.008%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PCD) (PMID: 22416021, 22499950, 24498942, 26373788). 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: 216542). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAH5 protein function. 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 Ambry Genetics, SCV002714541.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.R3539H pathogenic mutation (also known as c.10616G>A), located in coding exon 63 of the DNAH5 gene, results from a G to A substitution at nucleotide position 10616. The arginine at codon 3539 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in multiple unrelated individuals with primary ciliary dyskinesia who had a pathogenic mutation; phase was confirmed in trans in at least two individuals (Nakhleh N et al. Circulation, 2012 May;125:2232-42; Djakow J et al. Pediatr Pulmonol, 2012 Sep;47:864-75; Zariwala MA et al. Am J Hum Genet, 2013 Aug;93:336-45; Kim RH et al. Ann Am Thorac Soc, 2014 Mar;11:351-9; Raidt J et al. Hum Reprod, 2015 Dec;30:2871-80; Postema MC et al. Sci Rep, 2020 Feb;10:3677). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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: Jul 15, 2024

ClinVar

Relating variation to medicine