VCV000055840.27 - ClinVar

NM_145038.5(DRC1):c.352C>T (p.Gln118Ter)

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.

(8)

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_145038.5(DRC1):c.352C>T (p.Gln118Ter)

Variation ID: 55840 Accession: VCV000055840.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.3 2: 26421396 (GRCh38) [ NCBI UCSC ] 2: 26644264 (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 8, 2013	Oct 8, 2024	Dec 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_145038.5:c.352C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_659475.2:p.Gln118Ter	nonsense
NC_000002.12:g.26421396C>T
NC_000002.11:g.26644264C>T
NG_042824.1:g.24485C>T

Protein change

Q118*

Other names

Canonical SPDI

NC_000002.12:26421395:C:T

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

RNA degradation by nonsense-mediated decay; Variation Ontology [ VariO:0347]

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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

The Genome Aggregation Database (gnomAD) 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00031

The Genome Aggregation Database (gnomAD), exomes 0.00039

Exome Aggregation Consortium (ExAC) 0.00040

Links

ClinGen: CA214697 OMIM: 615288.0002 dbSNP: rs142371860 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.
DRC1		-	-	GRCh38 GRCh37	463	488

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 21	Pathogenic (2)	criteria provided, single submitter	Oct 31, 2018	RCV000049261.21
Primary ciliary dyskinesia	Pathogenic (1)	criteria provided, single submitter	Dec 15, 2023	RCV000549203.19
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 2, 2022	RCV000725468.14
not specified	no classifications from unflagged records (1)	no classifications from unflagged records	May 21, 2024	RCV000825030.13
Primary ciliary dyskinesia Primary ciliary dyskinesia 21	Pathogenic (1)	criteria provided, single submitter	-	RCV002254519.9
DRC1-related disorder	Likely pathogenic (1)	no assertion criteria provided	Jul 1, 2024	RCV004752736.1

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.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia 21 Primary ciliary dyskinesia (Autosomal recessive inheritance) Affected status: yes Allele origin: biparental	Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) Accession: SCV002525500.1 First in ClinVar: Jun 18, 2022 Last updated: Jun 18, 2022	Publications: PubMed (1) PubMed: 23354437 Comment: We analyzed the expression of DRC1 of a patient with this mutation and observed that mRNA was downregulated as well as its protein were also … (more) We analyzed the expression of DRC1 of a patient with this mutation and observed that mRNA was downregulated as well as its protein were also decreased. (less) Clinical Features: Female infertility (present) , Bronchiectasis (present) , Primary ciliary dyskinesia (present) , Abnormal respiratory motile cilium morphology (present) Sex: female Comment on evidence: We perform an ultrastructural analysis of of the axoneme of nasal cilia in a female patient with clinical features compatible with PCD and infertile and … (more) We perform an ultrastructural analysis of of the axoneme of nasal cilia in a female patient with clinical features compatible with PCD and infertile and revealed anomalies in both DA in all analyzed axoneme sections. We observed a reduction in the mean ciliary beat frequency, with the majority of the ciliated cells presenting dyskinetic movements. WES analysis revealed a homozygous null variant in the DRC1 gene (NM_145038.4: c.352C>T; p. Gln118*).Gene expression analysis by qPCR revealed a reduced mRNA expression of DRC1. In agreement, immunofluorescence analysis showed a very significant staining reduction of DRC1 in patient nasal cells. (less)
Pathogenic (Dec 15, 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: SCV000624510.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 23354437‚ 31960620 Comment: This sequence change creates a premature translational stop signal (p.Gln118) in the DRC1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gln118) in the DRC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DRC1 are known to be pathogenic (PMID: 23354437, 31960620). This variant is present in population databases (rs142371860, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23354437). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55840). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Nov 13, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000337157.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DRC1 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary ciliary dyskinesia 21 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893604.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jun 02, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002549228.2 First in ClinVar: Jul 23, 2022 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27996046, 23354437, 30487145, 12746204, 26582918, 34426522, 27535533) (less)
Pathogenic (Mar 01, 2013)	no assertion criteria provided Method: literature only	CILIARY DYSKINESIA, PRIMARY, 21, WITHOUT SITUS INVERSUS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000077514.4 First in ClinVar: Jul 05, 2013 Last updated: Jan 27, 2020	Publications: PubMed (2) PubMed: 12746204‚ 23354437 Comment on evidence: In affected members of 2 Swedish families with primary ciliary dyskinesia without situs inversus (CILD21; 615294), previously reported by Carlen et al. (2003), Wirschell et … (more) In affected members of 2 Swedish families with primary ciliary dyskinesia without situs inversus (CILD21; 615294), previously reported by Carlen et al. (2003), Wirschell et al. (2013) identified a homozygous c.352C-T transition in the DRC1 gene, resulting in a gln118-to-ter (Q118X) substitution. Respiratory cilia from 1 of these patients showed normal 9+2 ciliary microtubule organization with an absence of any observable N-DRC link. The inner and outer dynein arms appeared normal. (less)
Likely pathogenic (Jul 01, 2024)	no assertion criteria provided Method: clinical testing	DRC1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005364720.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The DRC1 c.352C>T variant is predicted to result in premature protein termination (p.Gln118). This variant has been reported in the homozygous state in three affected … (more) The DRC1 c.352C>T variant is predicted to result in premature protein termination (p.Gln118). This variant has been reported in the homozygous state in three affected individuals from two families with primary ciliary dyskinesia, and segregated with the disease in these families (Supplementary Figure 3, Wirschell et al. 2013. PubMed ID: 23354437). This variant is reported in 0.067% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 1 homozygote. Nonsense variants in DRC1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. (less)
Uncertain significance (Mar 16, 2018)	Flagged submission flagged submission (LMM Criteria) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000966227.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (1) PubMed: 23354437 Comment: Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln118X ( NM145038.2 c.352C>T) variant in DRC1 has been previously reported in 2 homozygou s individuals … (more) Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln118X ( NM145038.2 c.352C>T) variant in DRC1 has been previously reported in 2 homozygou s individuals with primary ciliary dyskinesia and segregated in 1 affected homoz ygous family member in 1 family (Wirschell 2013). Mutant studies and studies fro m patient cells with the p.Gln118X variant report an impact to protein function (Wirschell 2013). This variant has also been reported in ClinVar as likely patho genic (Variation ID#55840). It has been identified in 0.066% (83/126650) of Euro pean chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitut e.org; rs142371860). Although this variant has been seen in the general populati on, its frequency is low enough to be consistent with a recessive carrier freque ncy. This nonsense variant leads to a premature termination codon at position 11 8, which is predicted to lead to a truncated or absent protein. In summary, ther e is suspicion for a pathogenic role; however, the gene-disease association bet ween DRC1 is currently assessed at a moderate level. (less) Number of individuals with the variant: 1
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This sequence change creates a premature translational stop signal (p.Gln118*) in the DRC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DRC1 are known to be pathogenic (PMID: 23354437, 31960620). This variant is present in population databases (rs142371860, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23354437). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55840). For these reasons, this variant has been classified as Pathogenic.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27996046, 23354437, 30487145, 12746204, 26582918, 34426522, 27535533)

Comment:

The DRC1 c.352C>T variant is predicted to result in premature protein termination (p.Gln118*). This variant has been reported in the homozygous state in three affected individuals from two families with primary ciliary dyskinesia, and segregated with the disease in these families (Supplementary Figure 3, Wirschell et al. 2013. PubMed ID: 23354437). This variant is reported in 0.067% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 1 homozygote. Nonsense variants in DRC1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

Comment:

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln118X ( NM145038.2 c.352C>T) variant in DRC1 has been previously reported in 2 homozygou s individuals with primary ciliary dyskinesia and segregated in 1 affected homoz ygous family member in 1 family (Wirschell 2013). Mutant studies and studies fro m patient cells with the p.Gln118X variant report an impact to protein function (Wirschell 2013). This variant has also been reported in ClinVar as likely patho genic (Variation ID#55840). It has been identified in 0.066% (83/126650) of Euro pean chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitut e.org; rs142371860). Although this variant has been seen in the general populati on, its frequency is low enough to be consistent with a recessive carrier freque ncy. This nonsense variant leads to a premature termination codon at position 11 8, which is predicted to lead to a truncated or absent protein. In summary, ther e is suspicion for a pathogenic role; however, the gene-disease association bet ween DRC1 is currently assessed at a moderate level.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
RNA degradation by nonsense-mediated decay (VariO:0347)			Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) Accession: SCV002525500.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Copy number variation in DRC1 is the major cause of primary ciliary dyskinesia in the Japanese population.	Takeuchi K	Molecular genetics & genomic medicine	2020	PMID: 31960620
The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans.	Wirschell M	Nature genetics	2013	PMID: 23354437
Absence of nexin links as a possible cause of primary ciliary dyskinesia.	Carlén B	Ultrastructural pathology	2003	PMID: 12746204
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DRC1	-	-	-	-

Text-mined citations for rs142371860 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_145038.5(DRC1):c.352C>T (p.Gln118Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142371860 ...