This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in several patients with CCDC115 deficiency [PMID: 26833332]
ClinVar Genomic variation as it relates to human health
NM_032357.4(CCDC115):c.92T>C (p.Leu31Ser)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Genotype
- Identifiers
-
NM_032357.4(CCDC115):c.92T>C (p.Leu31Ser)
Variation ID: 218967 Accession: VCV000218967.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q21.1 2: 130342034 (GRCh38) [ NCBI UCSC ] 2: 131099607 (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 Feb 28, 2016 Jul 23, 2024 Dec 21, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_032357.4:c.92T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_115733.2:p.Leu31Ser missense NM_001321118.1:c.97-90T>C intron variant NM_001321119.2:c.87+5T>C intron variant NR_135548.2:n.131T>C non-coding transcript variant NC_000002.12:g.130342034A>G NC_000002.11:g.131099607A>G NG_046779.1:g.5777T>C Q96NT0:p.Leu31Ser - Protein change
- L31S
- Other names
- -
- Canonical SPDI
- NC_000002.12:130342033: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
- 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. |
|||
| CCDC115 | - | - |
GRCh38 GRCh37 |
45 | 94 | |
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
|
- | RCV000210795.1 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 21, 2023 | RCV000208585.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 18, 2023 | RCV001570443.5 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jul 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
CCDC115-CDG
Affected status: yes
Allele origin:
inherited
|
Baylor Genetics
Accession: SCV001528294.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in several patients with CCDC115 deficiency … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in several patients with CCDC115 deficiency [PMID: 26833332] (less)
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Pathogenic
(Jun 05, 2020)
|
criteria provided, single submitter
Method: clinical testing
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CCDC115-CDG
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001653114.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Comment:
The p.Leu31Ser variant in CCDC115 has been reported in 3 homozygous and 4 compound heterozygous (3 of which carried a loss of function allele in … (more)
The p.Leu31Ser variant in CCDC115 has been reported in 3 homozygous and 4 compound heterozygous (3 of which carried a loss of function allele in trans and one individual carried a missense) individuals with congenital disorder of glycosylation and segregated with disease in 2 affected relatives from 1 family (Jansen 2016 PMID:26833332, Girard 2018 PMID: 29759592). This variant has been identified in 3/128322 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies support an impact on protein function (Jansen 2016 PMID:26833332). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital disorder of glycosylation. ACMG/AMP Criteria applied: PP3, PS3_Supporting, PP1_Supporting, PM3_Very Strong. (less)
Number of individuals with the variant: 1
|
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Pathogenic
(Mar 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001794737.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26833332, 33413482, 29759592, 25902754) (less)
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Pathogenic
(Nov 18, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004293378.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 31 of the CCDC115 protein (p.Leu31Ser). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 31 of the CCDC115 protein (p.Leu31Ser). This variant is present in population databases (rs751325113, gnomAD 0.002%). This missense change has been observed in individual(s) with congenital disorder of glycosylation (PMID: 26833332, 29759592, 33413482). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218967). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
CCDC115-CDG
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005085896.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 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 congenital disorder of glycosylation, type IIo (CDG; MIM#616828). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 7 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 125 heterozygotes, 1 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least ten probands, both homozygotes and compound heterozygotes, diagnosed with CDG (PMIDs: 26833332, 29759592, 33413482). This variant has also been classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
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Congenital Disorders of Glycosylation type II
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center
Accession: SCV000257472.1
First in ClinVar: Apr 14, 2016 Last updated: Apr 14, 2016 |
Number of individuals with the variant: 6
Sex: mixed
Geographic origin: European
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Pathogenic
(Jun 21, 2019)
|
no assertion criteria provided
Method: literature only
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CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIo
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000264366.2
First in ClinVar: Feb 28, 2016 Last updated: Jun 24, 2019 |
Comment on evidence:
In 5 patients from 3 unrelated families with congenital disorder of glycosylation type IIo (CDG2O; 616828) Jansen et al. (2016) identified a homozygous c.92T-C transition … (more)
In 5 patients from 3 unrelated families with congenital disorder of glycosylation type IIo (CDG2O; 616828) Jansen et al. (2016) identified a homozygous c.92T-C transition (c.92T-C, NM_032357.3) in the CCDC115 gene, resulting in a leu31-to-ser (L31S) substitution at a highly conserved residue in the first predicted coiled-coil domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing in the first 2 families, segregated with the disorder in the families and was present at a very low frequency (8.253 x 10(-6)) in the ExAC database. An unrelated patient with a similar but more severe phenotype was found to be compound heterozygous for the L31S mutation and a heterozygous deletion that encompassed the entire CCDC115 gene. The 4 families with the L31S mutation were of distinct ethnic origin: Turkish, Italian, French, and Portuguese. Functional studies of the variant were not performed. (less)
|
Comment:
Comment:
The p.Leu31Ser variant in CCDC115 has been reported in 3 homozygous and 4 compound heterozygous (3 of which carried a loss of function allele in trans and one individual carried a missense) individuals with congenital disorder of glycosylation and segregated with disease in 2 affected relatives from 1 family (Jansen 2016 PMID:26833332, Girard 2018 PMID: 29759592). This variant has been identified in 3/128322 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies support an impact on protein function (Jansen 2016 PMID:26833332). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital disorder of glycosylation. ACMG/AMP Criteria applied: PP3, PS3_Supporting, PP1_Supporting, PM3_Very Strong.
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26833332, 33413482, 29759592, 25902754)
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 31 of the CCDC115 protein (p.Leu31Ser). This variant is present in population databases (rs751325113, gnomAD 0.002%). This missense change has been observed in individual(s) with congenital disorder of glycosylation (PMID: 26833332, 29759592, 33413482). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218967). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 congenital disorder of glycosylation, type IIo (CDG; MIM#616828). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 7 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 125 heterozygotes, 1 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least ten probands, both homozygotes and compound heterozygotes, diagnosed with CDG (PMIDs: 26833332, 29759592, 33413482). This variant has also been classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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 determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in several patients with CCDC115 deficiency [PMID: 26833332]
Comment:
The p.Leu31Ser variant in CCDC115 has been reported in 3 homozygous and 4 compound heterozygous (3 of which carried a loss of function allele in trans and one individual carried a missense) individuals with congenital disorder of glycosylation and segregated with disease in 2 affected relatives from 1 family (Jansen 2016 PMID:26833332, Girard 2018 PMID: 29759592). This variant has been identified in 3/128322 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies support an impact on protein function (Jansen 2016 PMID:26833332). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital disorder of glycosylation. ACMG/AMP Criteria applied: PP3, PS3_Supporting, PP1_Supporting, PM3_Very Strong.
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26833332, 33413482, 29759592, 25902754)
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 31 of the CCDC115 protein (p.Leu31Ser). This variant is present in population databases (rs751325113, gnomAD 0.002%). This missense change has been observed in individual(s) with congenital disorder of glycosylation (PMID: 26833332, 29759592, 33413482). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218967). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 congenital disorder of glycosylation, type IIo (CDG; MIM#616828). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 7 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 125 heterozygotes, 1 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least ten probands, both homozygotes and compound heterozygotes, diagnosed with CDG (PMIDs: 26833332, 29759592, 33413482). This variant has also been classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Liver manifestations in a cohort of 39 patients with congenital disorders of glycosylation: pin-pointing the characteristics of liver injury and proposing recommendations for follow-up. | Starosta RT | Orphanet journal of rare diseases | 2021 | PMID: 33413482 |
| CCDC115-CDG: A new rare and misleading inherited cause of liver disease. | Girard M | Molecular genetics and metabolism | 2018 | PMID: 29759592 |
| CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation. | Jansen JC | American journal of human genetics | 2016 | PMID: 26833332 |
Text-mined citations for rs751325113 ...
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.