ClinVar Genomic variation as it relates to human health
NM_000065.5(C6):c.2381+2T>C
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.
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(3); Likely pathogenic(5); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000065.5(C6):c.2381+2T>C
Variation ID: 379370 Accession: VCV000379370.59
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5p13.1 5: 41149933 (GRCh38) [ NCBI UCSC ] 5: 41150035 (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 Apr 4, 2013 Apr 6, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000065.5:c.2381+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001115131.4:c.2381+2T>C splice donor NC_000005.10:g.41149933A>G NC_000005.9:g.41150035A>G NG_011582.1:g.116506T>C LRG_29:g.116506T>C - Protein change
- Other names
- C6, IVS15DS, T-C, +2
- IVS15DS, T-C, +2
- Canonical SPDI
- NC_000005.10:41149932:A: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.
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0.00120 (G)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00221
The Genome Aggregation Database (gnomAD) 0.00242
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00308
1000 Genomes Project 0.00120
1000 Genomes Project 30x 0.00125
The Genome Aggregation Database (gnomAD), exomes 0.00219
Exome Aggregation Consortium (ExAC) 0.00231
- Comment on variant
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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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C6 | - | - |
GRCh38 GRCh37 |
454 | 476 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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. |
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Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Aug 7, 2023 | RCV000422743.30 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 15, 1996 | RCV002221153.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 15, 2023 | RCV002268046.12 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV002244875.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2023 | RCV003409589.4 |
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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Pathogenic
(Jun 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000927277.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
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Pathogenic
(Apr 28, 2022)
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criteria provided, single submitter
Method: research
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Complement component 6 deficiency
Affected status: yes
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-AGHI-WGS
Accession: SCV002515831.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG codes: PVS1, PS3, PS4_supporting, PM2_supporting, PP1
Number of individuals with the variant: 1
Clinical Features:
Hypotonia (present) , Ascites (present) , Retinopathy of prematurity (present)
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Uncertain significance
(Oct 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002295220.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change affects a donor splice site in intron 16 of the C6 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 16 of the C6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in C6 are known to be pathogenic (PMID: 17257682). This variant is present in population databases (rs76202909, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with C6 deficiency and recurrent infections. It has also been observed as heterozygous in individuals with subtotal C6 deficiency (C6SD), a condition in which individuals have decreased C6 levels, but are able to form a terminal complement complex, and do not appear to have increased susceptibility to Neisserial infections compared to the general population (PMID: 7535801, 8871666, 24378253). This variant is also known as an intron 15 variant. ClinVar contains an entry for this variant (Variation ID: 379370). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550458.4
First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023 |
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Likely pathogenic
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Complement component 6 deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Intergen, Intergen Genetics and Rare Diseases Diagnosis Center
Accession: SCV004030256.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
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Likely pathogenic
(Aug 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000516180.8
First in ClinVar: Mar 08, 2017 Last updated: Aug 31, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate that carriers present with lower than average C6 concentrations, however this variant allows for formation of a bactericidal-active, though less efficient, protein (Wurzner et al., 1995; Westra et al., 2014); This variant is associated with the following publications: (PMID: 22344438, 31453292, 31589614, 34426522, 36199823, 24378253, 7535801, 31345219) (less)
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Likely pathogenic
(Apr 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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C6-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004112324.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The C6 c.2381+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in patients with … (more)
The C6 c.2381+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in patients with C6 deficiency (Wurzner et al. 1995. PubMed ID: 7535801; Westra et al. 2014. PubMed ID: 24378253). In one report, individuals heterozygous for this variant have significantly reduced levels of C6 protein, but are not reported to be more susceptible to infection than individuals without this variant (Wurzner et al. 1995. PubMed ID: 7535801). This variant was also reported in the compound heterozygous state in a patient with relapsing bacterial and viral infections (Westra et al. 2014. PubMed ID: 24378253). This variant has been reported in up to ~0.38% of individuals (primarily within Europeans) in a large population database of presumably healthy individuals (http://gnomad.broadinstitute.org/variant/5-41150035-A-G?) and has conflicting interpretations in ClinVar ranging from uncertain significance to likely pathogenic to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/379370/). Taken together, we classify this variant as likely pathogenic. (less)
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Pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Complement component 6 deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004175762.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The invariant splice donor c.2381+2T>C variant in C6 gene has been observed in individuals with C6 deficiency (Westra et. al., 2014; Fernie et. al., 1996). … (more)
The invariant splice donor c.2381+2T>C variant in C6 gene has been observed in individuals with C6 deficiency (Westra et. al., 2014; Fernie et. al., 1996). This variant is also known as an intron 15 variant. The c.2381+2T>C variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.2% in gnomAD exomes database. This variant has been reported to the ClinVar database as Uncertain SIgnificance / Likely pathogenic / Pathogenic (multiple submitters). It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function and loss-of-function variants in C6 are known to be pathogenic (arham KL et. al., 2007). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Nov 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Complement component 6 deficiency
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048575.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024 |
Comment:
The C6 c.2381+2T>C variant (rs76202909) is reported in individuals with C6 deficiency, with one individual compound heterozygous for an additional C6 variant (Westra 2014, Wurzner … (more)
The C6 c.2381+2T>C variant (rs76202909) is reported in individuals with C6 deficiency, with one individual compound heterozygous for an additional C6 variant (Westra 2014, Wurzner 1995). The variant is reported in the ClinVar database (Variation ID: 379370) and is found in the general population with an overall allele frequency of 0.2% (626/282,244 alleles) in the Genome Aggregation Database (v2.1.1). This variant disrupts the canonical splice donor site of intron 16, which is likely to negatively impact gene function. Based on available information, this variant is classified as likely pathogenic. References: Westra D et al. Compound heterozygous mutations in the C6 gene of a child with recurrent infections. Mol Immunol. 2014 Apr;58(2):201-5. Wurzner R et al. Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6. J Clin Invest. 1995 Apr;95(4):1877-83. (less)
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Likely pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Complement component 6 deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807393.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548945.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The C6 c.2381+2T>C variant was identified in 2 of 266 chromosomes (frequency: 0.0075) from a cohort of 133 infants with critical congenital heart disease (Russell_2019_PMID:31453292). … (more)
The C6 c.2381+2T>C variant was identified in 2 of 266 chromosomes (frequency: 0.0075) from a cohort of 133 infants with critical congenital heart disease (Russell_2019_PMID:31453292). The variant was also identified in an infant patient with recurrent infections; the patient was compound heterozygous for the c.2381+2T>C variant (paternally inherited; also found in the patient's sister) and a p.C867R variant (maternally inherited). The patient's C6 levels were ~5% of wildtype, while the father and sister carrying only the c.2381+2T>C variant had 50% C6 levels compared to wildtype (Westra_2014_PMID:24378253). Three patients with subtotal C6 deficiency from 2 families were previously found to be heterozygous for the c.2381+2T>C variant. The C6 concentration in these patients was found to be 1-2% of the normal mean but was not completely absent; a smaller C6 product was identified that is 14% shorter than normal C6 and was attributed to the c.2381+2T>C variant which is expected to lead to abnormal splicing and a premature stop codon 17 amino acids downstream of the intron-exon boundary (Wurzner_1995_PMID:7535801). The variant was identified in dbSNP (ID: rs76202909), ClinVar (classified as pathogenic by Blueprint Genetics and uncertain significance by GeneDx) and LOVD 3.0 (classified as likely pathogenic and pathogenic by VKGL-NL). The variant was identified in control databases in 626 of 282244 chromosomes at a frequency of 0.002218 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 491 of 128722 chromosomes (freq: 0.003814), Other in 23 of 7196 chromosomes (freq: 0.003196), South Asian in 47 of 30612 chromosomes (freq: 0.001535), European (Finnish) in 20 of 25096 chromosomes (freq: 0.000797), Latino in 28 of 35384 chromosomes (freq: 0.000791) and African in 17 of 24966 chromosomes (freq: 0.000681), but was not observed in the Ashkenazi Jewish or East Asian populations. The c.2381+2T>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740271.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930499.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958729.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968499.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Oct 15, 1996)
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no assertion criteria provided
Method: literature only
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C6 DEFICIENCY, SUBTOTAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033138.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022 |
Comment on evidence:
Individuals with subtotal C6 deficiency (C6D; 612446) possess a C6 molecule that is 14% shorter than normal C6 and present in low but detectable concentrations … (more)
Individuals with subtotal C6 deficiency (C6D; 612446) possess a C6 molecule that is 14% shorter than normal C6 and present in low but detectable concentrations in the serum (1 to 2% of the normal mean). Wurzner et al. (1995) identified a mutation in 3 individuals with subtotal C6 deficiency from 2 families. All 3 had an abnormal 5-prime splice donor site of intron 15 predicted to prevent splicing. An in-frame stop codon was found 17 codons downstream from the intron boundary, which would lead to a truncated polypeptide 140 amino acids (13.5%) smaller than the normal C6. All 3 subjects were probably heterozygous for both subtotal C6 and complete C6 deficiency. The splice donor site of intron 15 showed a change from AG/gt to AG/gc. In individuals with combined subtotal deficiency of C6 and C7, Fernie et al. (1996) identified this mutation and a C7 mutation (arg499 to ser; 217070.0003) on a characteristic haplotype. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Compound heterozygous mutations in the C6 gene of a child with recurrent infections. | Westra D | Molecular immunology | 2014 | PMID: 24378253 |
Prevalence of mutations leading to complete C6 deficiency (C6Q0) in the Western Cape, South Africa and detection of novel mutations leading to C6Q0 in an Irish family. | Parham KL | Molecular immunology | 2007 | PMID: 17257682 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Molecular bases of combined subtotal deficiencies of C6 and C7: their effects in combination with other C6 and C7 deficiencies. | Fernie BA | Journal of immunology (Baltimore, Md. : 1950) | 1996 | PMID: 8871666 |
Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6. | Würzner R | The Journal of clinical investigation | 1995 | PMID: 7535801 |
Text-mined citations for rs76202909 ...
HelpRecord last updated Apr 20, 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.
NCBI staff provided an HGVS expression for allelic variant 217050.0002 from the sequence reported in Figure 4 of the paper by Wurzner et al., 1995 (PubMed 7535801).