VCV000454795.20 - ClinVar

NM_001369.3(DNAH5):c.6763C>T (p.Arg2255Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001369.3(DNAH5):c.6763C>T (p.Arg2255Ter)

Variation ID: 454795 Accession: VCV000454795.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5p15.2 5: 13820424 (GRCh38) [ NCBI UCSC ] 5: 13820533 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 26, 2017	Aug 25, 2024	Dec 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001369.3:c.6763C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001360.1:p.Arg2255Ter	nonsense
NC_000005.10:g.13820424G>A
NC_000005.9:g.13820533G>A
NG_013081.2:g.129057C>T

Protein change

R2255*

Other names

Canonical SPDI

NC_000005.10:13820423:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA3203285 dbSNP: rs745918507 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DNAH5		-	-	GRCh38 GRCh37	5638	5885

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Primary ciliary dyskinesia	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 20, 2023	RCV000549276.13
Primary ciliary dyskinesia 3	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 8, 2022	RCV000670288.5
Infertility disorder	Pathogenic (1)	no assertion criteria provided	-	RCV001327941.2
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 13, 2022	RCV002223859.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Oct 27, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Primary ciliary dyskinesia 3 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000795122.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 27637300
Likely pathogenic (May 05, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia Affected status: yes Allele origin: germline	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Accession: SCV001431619.2 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020	Publications: PubMed (1) PubMed: 27637300 Zygosity: Compound Heterozygote
Pathogenic (Mar 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502685.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (4) PubMed: 27637300‚ 31589614‚ 31879361‚ 30293990 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Jul 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia 3 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807614.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated, PM3 moderated Number of individuals with the variant: 1 Clinical Features: Poor suck (present) , Cough (present) , Neonatal asphyxia (present) , Neonatal sepsis (present) , Neonatal respiratory distress (present) , Situs inversus (present) , Prolonged … (more) Poor suck (present) , Cough (present) , Neonatal asphyxia (present) , Neonatal sepsis (present) , Neonatal respiratory distress (present) , Situs inversus (present) , Prolonged neonatal jaundice (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Dec 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia Affected status: yes Allele origin: maternal	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre Accession: SCV004176750.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (3) PubMed: 27637300‚ 31879361‚ 30293990 Comment: ACMG: PVS1, PM2, PM3, PP5 Number of individuals with the variant: 1 Age: 10-19 years Sex: female Ethnicity/Population group: European Caucasoid
Pathogenic (Jun 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia 3 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003823279.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Dec 20, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Primary ciliary dyskinesia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000624281.5 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 11788826‚ 16627867‚ 27637300 Comment: This sequence change creates a premature translational stop signal (p.Arg2255) in the DNAH5 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg2255) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). This variant is present in population databases (rs745918507, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 27637300). ClinVar contains an entry for this variant (Variation ID: 454795). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197751.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (-)	no assertion criteria provided Method: provider interpretation	Infertility disorder Affected status: yes Allele origin: germline	MAGI's Lab - Research, MAGI Group Accession: SCV001432719.1 First in ClinVar: Mar 18, 2021 Last updated: Mar 18, 2021
Pathogenic (Aug 13, 2020)	no assertion criteria provided Method: clinical testing	Primary ciliary dyskinesia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002080884.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change creates a premature translational stop signal (p.Arg2255*) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). This variant is present in population databases (rs745918507, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 27637300). ClinVar contains an entry for this variant (Variation ID: 454795). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort.	Fassad MR	Journal of medical genetics	2020	PMID: 31879361
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies.	Quinlan-Jones E	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30293990
Diagnosis of Primary Ciliary Dyskinesia by a Targeted Next-Generation Sequencing Panel: Molecular and Clinical Findings in Italian Patients.	Boaretto F	The Journal of molecular diagnostics : JMD	2016	PMID: 27637300
DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects.	Hornef N	American journal of respiratory and critical care medicine	2006	PMID: 16627867
Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry.	Olbrich H	Nature genetics	2002	PMID: 11788826

Text-mined citations for rs745918507 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001369.3(DNAH5):c.6763C>T (p.Arg2255Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs745918507 ...