This sequence change creates a premature translational stop signal (p.Arg116*) in the C9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C9 are known to be pathogenic (PMID: 9144525, 9570574). This variant is present in population databases (rs121909592, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with complement component 9 (C9) deficiency (PMID: 9570574, 9703418, 12596049, 22190594). It is commonly reported in individuals of East Asian ancestry (PMID: 9570574, 9703418, 12596049, 22190594). This variant is also known as Arg95*. ClinVar contains an entry for this variant (Variation ID: 17040). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001737.5(C9):c.346C>T (p.Arg116Ter)
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.
(7)
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/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001737.5(C9):c.346C>T (p.Arg116Ter)
Variation ID: 17040 Accession: VCV000017040.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5p13.1 5: 39341276 (GRCh38) [ NCBI UCSC ] 5: 39341378 (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 Apr 4, 2013 Jan 25, 2025 Oct 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001737.5:c.346C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001728.1:p.Arg116Ter nonsense NC_000005.10:g.39341276G>A NC_000005.9:g.39341378G>A NG_009894.1:g.28278C>T LRG_32:g.28278C>T LRG_32t1:c.346C>T LRG_32p1:p.Arg116Ter - Protein change
- R116*
- Other names
-
C9, ARG95TER
R95*
- Canonical SPDI
- NC_000005.10:39341275:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00300 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00300
The Genome Aggregation Database (gnomAD) 0.00026
Trans-Omics for Precision Medicine (TOPMed) 0.00034
Exome Aggregation Consortium (ExAC) 0.00083
1000 Genomes Project 30x 0.00297
- 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. |
|||
| C9 | - | - |
GRCh38 GRCh37 |
328 | 353 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 9, 2024 | RCV000018568.34 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 2, 2024 | RCV001851916.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 2, 2024 | RCV005042062.1 |
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. |
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|---|---|---|---|---|---|
|
Pathogenic
(Oct 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Complement component 9 deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018021.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Complement component 9 deficiency
Age related macular degeneration 15
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV005673449.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
|
|
|
Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002228932.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg116*) in the C9 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg116*) in the C9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C9 are known to be pathogenic (PMID: 9144525, 9570574). This variant is present in population databases (rs121909592, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with complement component 9 (C9) deficiency (PMID: 9570574, 9703418, 12596049, 22190594). It is commonly reported in individuals of East Asian ancestry (PMID: 9570574, 9703418, 12596049, 22190594). This variant is also known as Arg95*. ClinVar contains an entry for this variant (Variation ID: 17040). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Complement component 9 deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005399820.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with C9 deficiency (MIM#613825). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 224 heterozygotes, 0 homozygotes; v3: 87 heterozygotes, 1 homozygote). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with C9 deficiency and is regarded as a Japanese founder variant (ClinVar, PMID: 9570574). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Complement component 9 deficiency
Affected status: yes
Allele origin:
germline
|
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005417812.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PVS1+PM3
|
|
|
Pathogenic
(Mar 01, 2003)
|
no assertion criteria provided
Method: literature only
|
C9 DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038850.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Horiuchi et al. (1998) found that 8 of 10 unrelated Japanese subjects with C9 deficiency (613825) were homozygous for a C-to-T transition at nucleotide 343, … (more)
Horiuchi et al. (1998) found that 8 of 10 unrelated Japanese subjects with C9 deficiency (613825) were homozygous for a C-to-T transition at nucleotide 343, which converted codon 95 from CGA (arg) to TGA (stop). Two other patients were heterozygous for the R95X mutation; one of these had a C507Y (120940.0005) substitution, while the genetic defect in the other allele of the second heterozygote remained unknown. Kira et al. (1998) likewise found that all 4 Japanese C9-deficient patients who had suffered from meningococcal meningitis had this CGA (arg)-to-TGA (stop) mutation. Ichikawa et al. (2001) found this mutation in a 28-year-old Japanese woman with C9 deficiency and dermatomyositis. Whereas levels of serum hemolytic complement (CH50) are characteristically normal or elevated in patients with dermatomyositis, this patient showed markedly depressed levels of CH50. This case demonstrated that the muscle lesions of dermatomyositis can occur in the presence of a complement defect that would prevent the formation of the C5b-9 membrane attack complex. The R95X mutation is responsible for most Japanese C9 deficiency cases, with a carrier frequency of 6.7%. Khajoee et al. (2003) showed that in Koreans and Chinese, the R95X carrier frequencies were 2.0% and 1.0%, respectively. The founder effect found in East Asians (Japanese, Koreans, and Chinese) but not in Caucasians, as well as the haplotype sharing in only a small chromosomal region, suggested that the R95X mutation is ancient and occurred after the divergence of East Asians and Caucasians, and before migration of the Yayoi people to Japan. Because the mortality of meningococcal infections in complement-deficient patients is lower than that in normal individuals, a founder effect and a selective advantage in isolation might be the main reasons for the high frequency of the R95X mutation in Japan. (less)
|
|
|
Pathogenic
(Jan 06, 2020)
|
no assertion criteria provided
Method: curation
|
Complement component 9 deficiency
Affected status: unknown
Allele origin:
germline
|
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142345.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
NM_001737.3:c.346C>T in the C9 gene has an allele frequency of 0.01 in East Asian subpopulation in the gnomAD database. The C9 c.346C>T (p.Arg116*) variant has … (more)
NM_001737.3:c.346C>T in the C9 gene has an allele frequency of 0.01 in East Asian subpopulation in the gnomAD database. The C9 c.346C>T (p.Arg116*) variant has been reported in five Japanese C9-deficient patients in homozygous states (PMID: 9703418; 11359403). Another study revealed that eight of the 10 C9D subjects were homozygous for this variant, which was assumed to be a founder mutation in Japanese (PMID: 9570574). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PS4. (less)
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with C9 deficiency (MIM#613825). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 224 heterozygotes, 0 homozygotes; v3: 87 heterozygotes, 1 homozygote). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with C9 deficiency and is regarded as a Japanese founder variant (ClinVar, PMID: 9570574). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
PVS1+PM3
Comment:
NM_001737.3:c.346C>T in the C9 gene has an allele frequency of 0.01 in East Asian subpopulation in the gnomAD database. The C9 c.346C>T (p.Arg116*) variant has been reported in five Japanese C9-deficient patients in homozygous states (PMID: 9703418; 11359403). Another study revealed that eight of the 10 C9D subjects were homozygous for this variant, which was assumed to be a founder mutation in Japanese (PMID: 9570574). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PS4.
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 sequence change creates a premature translational stop signal (p.Arg116*) in the C9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C9 are known to be pathogenic (PMID: 9144525, 9570574). This variant is present in population databases (rs121909592, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with complement component 9 (C9) deficiency (PMID: 9570574, 9703418, 12596049, 22190594). It is commonly reported in individuals of East Asian ancestry (PMID: 9570574, 9703418, 12596049, 22190594). This variant is also known as Arg95*. ClinVar contains an entry for this variant (Variation ID: 17040). For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with C9 deficiency (MIM#613825). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 224 heterozygotes, 0 homozygotes; v3: 87 heterozygotes, 1 homozygote). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with C9 deficiency and is regarded as a Japanese founder variant (ClinVar, PMID: 9570574). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
PVS1+PM3
Comment:
NM_001737.3:c.346C>T in the C9 gene has an allele frequency of 0.01 in East Asian subpopulation in the gnomAD database. The C9 c.346C>T (p.Arg116*) variant has been reported in five Japanese C9-deficient patients in homozygous states (PMID: 9703418; 11359403). Another study revealed that eight of the 10 C9D subjects were homozygous for this variant, which was assumed to be a founder mutation in Japanese (PMID: 9570574). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PS4.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| C9-R95X polymorphism in patients with neovascular age-related macular degeneration. | Nishiguchi KM | Investigative ophthalmology & visual science | 2012 | PMID: 22190594 |
| Founder effect of the C9 R95X mutation in Orientals. | Khajoee V | Human genetics | 2003 | PMID: 12596049 |
| Hereditary complement (C9) deficiency associated with dermatomyositis. | Ichikawa E | The British journal of dermatology | 2001 | PMID: 11359403 |
| Nonsense mutation in exon 4 of human complement C9 gene is the major cause of Japanese complement C9 deficiency. | Kira R | Human genetics | 1998 | PMID: 9703418 |
| A non-sense mutation at Arg95 is predominant in complement 9 deficiency in Japanese. | Horiuchi T | Journal of immunology (Baltimore, Md. : 1950) | 1998 | PMID: 9570574 |
| The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure. | Witzel-Schlömp K | Journal of immunology (Baltimore, Md. : 1950) | 1997 | PMID: 9144525 |
Text-mined citations for rs121909592 ...
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 Jan 26, 2025
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.