This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
ClinVar Genomic variation as it relates to human health
NM_012472.6(DNAAF11):c.436G>C (p.Asp146His)
Germline
Classification
Help
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.
(9)
Help
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_012472.6(DNAAF11):c.436G>C (p.Asp146His)
Variation ID: 39798 Accession: VCV000039798.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q24.22 8: 132632957 (GRCh38) [ NCBI UCSC ] 8: 133645203 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 1, 2013 Aug 25, 2024 Dec 11, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_012472.6:c.436G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036604.2:p.Asp146His missense NM_001321961.2:c.436G>C NP_001308890.1:p.Asp146His missense NM_001321962.2:c.190G>C NP_001308891.1:p.Asp64His missense NM_001321963.2:c.76G>C NP_001308892.1:p.Asp26His missense NM_001321964.2:c.76G>C NP_001308893.1:p.Asp26His missense NM_001321965.2:c.76G>C NP_001308894.1:p.Asp26His missense NM_001321966.2:c.76G>C NP_001308895.1:p.Asp26His missense NR_073525.3:n.488G>C non-coding transcript variant NC_000008.11:g.132632957C>G NC_000008.10:g.133645203C>G NG_033068.1:g.47661G>C Q86X45:p.Asp146His - Protein change
- D146H, D64H, D26H
- Other names
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LRRC6, ASP146HIS (rs200321595)
- Canonical SPDI
- NC_000008.11:132632956:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe 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.
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The Genome Aggregation Database (gnomAD) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00016
Exome Aggregation Consortium (ExAC) 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| DNAAF11 | - | - |
GRCh38 GRCh37 |
250 | 312 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Apr 24, 2021 | RCV001731475.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 13, 2022 | RCV004696644.1 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 11, 2023 | RCV002460894.6 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Nov 2, 2023 | RCV000033020.18 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 19
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Hadassah Hebrew University Medical Center
Accession: SCV004099504.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
|
|
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Pathogenic
(Aug 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 19
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368647.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
|
|
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Pathogenic
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
Affected status: yes
Allele origin:
germline
|
Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre
Accession: SCV004176743.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
ACMG: PP5, PP3, PM2, BP1. The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 39798)
Number of individuals with the variant: 1
Age: 20-29 years
Sex: female
Ethnicity/Population group: European Caucasoid
|
|
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Pathogenic
(Nov 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 19
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000772163.6
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 146 of the LRRC6 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 146 of the LRRC6 protein (p.Asp146His). This variant is present in population databases (rs200321595, gnomAD 0.03%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23122589, 23527195, 23891469). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39798). 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) performed at Invitae indicates that this missense variant is expected to disrupt LRRC6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LRRC6 function (PMID: 23527195). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002755383.3
First in ClinVar: Dec 03, 2022 Last updated: May 01, 2024 |
Comment:
The p.D146H pathogenic mutation (also known as c.436G>C), located in coding exon 5 of the LRRC6 gene, results from a G to C substitution at … (more)
The p.D146H pathogenic mutation (also known as c.436G>C), located in coding exon 5 of the LRRC6 gene, results from a G to C substitution at nucleotide position 436. The aspartic acid at codon 146 is replaced by histidine, an amino acid with similar properties. This mutation was identified in the compound heterozygous state in two individuals with primary ciliary dyskinesia (PCD) and absent dynein arms (Kott E et al. Am. J. Hum. Genet., 2012 Nov;91:958-64; Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45). It was also identified in the homozyogus state is 5 individuals with PCD from 2 unrelated families; all five individuals had absent dynein arms and three had situs abnormalities (Horani A et al. PLoS ONE, 2013 Mar;8:e59436). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
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Pathogenic
(Jul 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197745.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
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Pathogenic
(Nov 02, 2012)
|
no assertion criteria provided
Method: literature only
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CILIARY DYSKINESIA, PRIMARY, 19
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000056800.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 25, 2015 |
Comment on evidence:
In a European male with primary ciliary dyskinesia-19 (CILD19; 614935), Kott et al. (2012) identified compound heterozygosity for 2 mutations in the LRRC6 gene: a … (more)
In a European male with primary ciliary dyskinesia-19 (CILD19; 614935), Kott et al. (2012) identified compound heterozygosity for 2 mutations in the LRRC6 gene: a 436G-C transversion in exon 5, resulting in an asp146-to-his (D146H) substitution at a highly conserved residue in the LRRcap, and a 2-bp deletion (598delAA; 614930.0001). The D146H mutation was predicted to affect protein conformation. The 436G-C mutation has been reported as a rare SNP (rs200321595) with a low allele frequency (0.00023). The patient had a chronic sinopulmonary syndrome, asthenospermia, and situs inversus associated with lack of the inner and outer ciliary dynein arms. (less)
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Pathogenic
(Apr 24, 2021)
|
no assertion criteria provided
Method: research
|
Heterotaxy
Affected status: yes
Allele origin:
inherited
|
Pediatric Genetics Clinic, Sheba Medical Center
Accession: SCV001572803.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Number of individuals with the variant: 1
Clinical Features:
Transposition of the great arteries (present) , Pulmonary valve atresia (present) , Unbalanced atrioventricular canal defect (present) , Double outlet right ventricle (present)
Secondary finding: no
|
|
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not provided
(-)
|
no classification provided
Method: literature only
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Primary ciliary dyskinesia 19
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000086955.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
ACMG: PP5, PP3, PM2, BP1. The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 39798)
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 146 of the LRRC6 protein (p.Asp146His). This variant is present in population databases (rs200321595, gnomAD 0.03%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23122589, 23527195, 23891469). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39798). 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) performed at Invitae indicates that this missense variant is expected to disrupt LRRC6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LRRC6 function (PMID: 23527195). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.D146H pathogenic mutation (also known as c.436G>C), located in coding exon 5 of the LRRC6 gene, results from a G to C substitution at nucleotide position 436. The aspartic acid at codon 146 is replaced by histidine, an amino acid with similar properties. This mutation was identified in the compound heterozygous state in two individuals with primary ciliary dyskinesia (PCD) and absent dynein arms (Kott E et al. Am. J. Hum. Genet., 2012 Nov;91:958-64; Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45). It was also identified in the homozyogus state is 5 individuals with PCD from 2 unrelated families; all five individuals had absent dynein arms and three had situs abnormalities (Horani A et al. PLoS ONE, 2013 Mar;8:e59436). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
Comment:
ACMG: PP5, PP3, PM2, BP1. The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 39798)
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 146 of the LRRC6 protein (p.Asp146His). This variant is present in population databases (rs200321595, gnomAD 0.03%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23122589, 23527195, 23891469). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39798). 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) performed at Invitae indicates that this missense variant is expected to disrupt LRRC6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LRRC6 function (PMID: 23527195). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.D146H pathogenic mutation (also known as c.436G>C), located in coding exon 5 of the LRRC6 gene, results from a G to C substitution at nucleotide position 436. The aspartic acid at codon 146 is replaced by histidine, an amino acid with similar properties. This mutation was identified in the compound heterozygous state in two individuals with primary ciliary dyskinesia (PCD) and absent dynein arms (Kott E et al. Am. J. Hum. Genet., 2012 Nov;91:958-64; Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45). It was also identified in the homozyogus state is 5 individuals with PCD from 2 unrelated families; all five individuals had absent dynein arms and three had situs abnormalities (Horani A et al. PLoS ONE, 2013 Mar;8:e59436). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Primary Ciliary Dyskinesia. | Adam MP | - | 2019 | PMID: 20301301 |
| ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. | Zariwala MA | American journal of human genetics | 2013 | PMID: 23891469 |
| LRRC6 mutation causes primary ciliary dyskinesia with dynein arm defects. | Horani A | PloS one | 2013 | PMID: 23527195 |
| Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia. | Kott E | American journal of human genetics | 2012 | PMID: 23122589 |
Text-mined citations for rs200321595 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.