VCV000916128.5 - ClinVar

NM_001277115.2(DNAH11):c.13373C>T (p.Pro4458Leu)

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.

(4)

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_001277115.2(DNAH11):c.13373C>T (p.Pro4458Leu)

Variation ID: 916128 Accession: VCV000916128.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p15.3 7: 21901076 (GRCh38) [ NCBI UCSC ] 7: 21940694 (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	Nov 28, 2020	Apr 15, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001277115.2:c.13373C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001264044.1:p.Pro4458Leu	missense
NM_018719.5:c.*1246G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_001127370.3:c.*1246G>A		3 prime UTR
NM_001127371.3:c.*1246G>A		3 prime UTR
NC_000007.14:g.21901076C>T
NC_000007.13:g.21940694C>T
NG_012886.2:g.362862C>T

... more HGVS ... less HGVS

Protein change

P4458L

Other names

Canonical SPDI

NC_000007.14:21901075:C:T

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) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00010

Exome Aggregation Consortium (ExAC) 0.00013

Links

dbSNP: rs72658835 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.
CDCA7L		-	-	GRCh38 GRCh37	30	208
DNAH11		-	-	GRCh38 GRCh37	5399	5781

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 7	Pathogenic (1)	criteria provided, single submitter	Dec 20, 2020	RCV001594411.2
Primary ciliary dyskinesia	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV001268926.5

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 (Apr 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Primary ciliary dyskinesia Affected status: yes, no Allele origin: inherited, unknown	Centre for Genomic and Experimental Medicine, University of Edinburgh Accession: SCV001334263.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Observation 1: Zygosity: Homozygote Observation 2: Zygosity: Single Heterozygote Observation 3: Zygosity: Single Heterozygote
Pathogenic (Dec 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia 7 Affected status: yes Allele origin: germline	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital Accession: SCV001499938.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Publications: PubMed (4) PubMed: 22184204‚ 29997923‚ 32622824‚ 32502479 Number of individuals with the variant: 1 Age: 0-9 years Sex: male Ethnicity/Population group: East Asia Geographic origin: China
Likely pathogenic (Feb 25, 2020)	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: SCV001574405.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (2) PubMed: 22184204‚ 29997923 Comment: This sequence change replaces proline with leucine at codon 4458 of the DNAH11 protein (p.Pro4458Leu). The proline residue is moderately conserved and there is a … (more) This sequence change replaces proline with leucine at codon 4458 of the DNAH11 protein (p.Pro4458Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs72658835, ExAC 0.05%). This variant has been observed in individual(s) with clinical features of DNAH11-related conditions (PMID: 22184204, 29997923, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Not Available; PolyPhen-2: Probably Damaging; Align-GVGD: Not Available). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Likely pathogenic (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812541.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (6) PubMed: 22184204‚ 29997923‚ 32502479‚ 33942430‚ 34133440‚ 34556108 Comment: This sequence change in DNAH11 is predicted to replace proline with leucine at codon 4458, p.(Pro4458Leu). The proline residue is highly conserved (100 vertebrates, Multiz … (more) This sequence change in DNAH11 is predicted to replace proline with leucine at codon 4458, p.(Pro4458Leu). The proline residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the C-terminal domain. There is a moderate physicochemical difference between proline and leucine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.03% (24/91,062 alleles) in the South Asian population, which is consistent with recessive disease. The variant has been detected in the homozygous and compound heterozygous state in at least 6 probands with primary ciliary dyskinesia (PCD) and/or complex congenital heart defects, confirmed in trans with a second pathogenic variant in at least one individual (PMID: 22184204, 29997923, 32502479, 33942430, 34133440, 34556108). The variant segregates with PCD in at least one family and is associated with incomplete penetrance for congenital heart defects in one family (PMID: 32502479, 34133440). Computational evidence is uninformative for the missense substitution (REVEL = 0.38). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PM2_Supporting, PP1. (less)

Comment:

This sequence change replaces proline with leucine at codon 4458 of the DNAH11 protein (p.Pro4458Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs72658835, ExAC 0.05%). This variant has been observed in individual(s) with clinical features of DNAH11-related conditions (PMID: 22184204, 29997923, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Not Available; PolyPhen-2: Probably Damaging; Align-GVGD: Not Available). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

This sequence change in DNAH11 is predicted to replace proline with leucine at codon 4458, p.(Pro4458Leu). The proline residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the C-terminal domain. There is a moderate physicochemical difference between proline and leucine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.03% (24/91,062 alleles) in the South Asian population, which is consistent with recessive disease. The variant has been detected in the homozygous and compound heterozygous state in at least 6 probands with primary ciliary dyskinesia (PCD) and/or complex congenital heart defects, confirmed in trans with a second pathogenic variant in at least one individual (PMID: 22184204, 29997923, 32502479, 33942430, 34133440, 34556108). The variant segregates with PCD in at least one family and is associated with incomplete penetrance for congenital heart defects in one family (PMID: 32502479, 34133440). Computational evidence is uninformative for the missense substitution (REVEL = 0.38). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PM2_Supporting, PP1.

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
Whole genome sequencing in the diagnosis of primary ciliary dyskinesia.	Wheway G	BMC medical genomics	2021	PMID: 34556108
DNAH11 compound heterozygous variants cause heterotaxy and congenital heart disease.	Xia H	PloS one	2021	PMID: 34133440
Exome sequencing as the first-tier test for pediatric respiratory diseases: A single-center study.	Hao C	Human mutation	2021	PMID: 33942430
WITHDRAWN: Clinical and Genetic Spectrum of Children with Primary Ciliary Dyskinesia in China.	Guan Y	Chest	2020	PMID: 32622824
Clinical and Genetic Spectrum of Children with Primary Ciliary Dyskinesia in China.	Guo Z	The Journal of pediatrics	2020	PMID: 32502479
Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis.	Guan WJ	Journal of thoracic disease	2018	PMID: 29997923
Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure.	Knowles MR	Thorax	2012	PMID: 22184204

Text-mined citations for rs72658835 ...

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_001277115.2(DNAH11):c.13373C>T (p.Pro4458Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72658835 ...