NM_001369.3(DNAH5):c.8827C>T (p.Arg2943Cys) AND Primary ciliary dyskinesia

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Nov 14, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001221360.13

Allele description [Variation Report for NM_001369.3(DNAH5):c.8827C>T (p.Arg2943Cys)]

NM_001369.3(DNAH5):c.8827C>T (p.Arg2943Cys)

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.8827C>T (p.Arg2943Cys)

HGVS:

NC_000005.10:g.13780953G>A
NG_013081.2:g.168528C>T
NM_001369.3:c.8827C>TMANE SELECT
NP_001360.1:p.Arg2943Cys
NP_001360.1:p.Arg2943Cys
NC_000005.9:g.13781062G>A
NC_000005.9:g.13781062G>A
NM_001369.2:c.8827C>T

Protein change:

R2943C

Links:

dbSNP: rs758324905

NCBI 1000 Genomes Browser:

rs758324905

Molecular consequence:

NM_001369.3:c.8827C>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001393400	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002080835	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jul 31, 2020)	germline	clinical testing
SCV002683398	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 7, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001393400

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 14, 2023)

germline

clinical testing

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

SCV002080835

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Jul 31, 2020)

germline

clinical testing

SCV002683398

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 7, 2022)

germline

clinical testing

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001393400.4

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

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2943 of the DNAH5 protein (p.Arg2943Cys). This variant is present in population databases (rs758324905, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of DNAH5-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 949808). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg2943 amino acid residue in DNAH5. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Natera, Inc., SCV002080835.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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, SCV002683398.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The p.R2943C variant (also known as c.8827C>T), located in coding exon 53 of the DNAH5 gene, results from a C to T substitution at nucleotide position 8827. The arginine at codon 2943 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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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