NM_032357.4(CCDC115):c.92T>C (p.Leu31Ser) AND CCDC115-CDG

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 21, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000208585.9

Allele description [Variation Report for NM_032357.4(CCDC115):c.92T>C (p.Leu31Ser)]

NM_032357.4(CCDC115):c.92T>C (p.Leu31Ser)

Gene:

CCDC115:coiled-coil domain containing 115 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q21.1

Genomic location:

Preferred name:

NM_032357.4(CCDC115):c.92T>C (p.Leu31Ser)

HGVS:

NC_000002.12:g.130342034A>G
NG_046779.1:g.5777T>C
NM_001321118.1:c.97-90T>C
NM_001321119.2:c.87+5T>C
NM_032357.4:c.92T>CMANE SELECT
NP_115733.2:p.Leu31Ser
NC_000002.11:g.131099607A>G
NM_032357.2:c.92T>C
NM_032357.3:c.92T>C
NR_135548.2:n.131T>C
Q96NT0:p.Leu31Ser

Protein change:

L31S; LEU31SER

Links:

UniProtKB: Q96NT0#VAR_075753; OMIM: 613734.0001; dbSNP: rs751325113

NCBI 1000 Genomes Browser:

rs751325113

Molecular consequence:

NM_001321118.1:c.97-90T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001321119.2:c.87+5T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_032357.4:c.92T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_135548.2:n.131T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: CCDC115-CDG
Synonyms:: CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIo; CDG IIo
Identifiers:: MONDO: MONDO:0014789; MedGen: C4225191; OMIM: 616828

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000264366	OMIM	no assertion criteria provided	Pathogenic (Jun 21, 2019)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001528294	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 11, 2018)	inherited	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26833332, 25741868
SCV001653114	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jun 5, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26833332, 29759592, 24033266
SCV005085896	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26833332, 29759592, 33413482, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation.

Jansen JC, Cirak S, van Scherpenzeel M, Timal S, Reunert J, Rust S, Pérez B, Vicogne D, Krawitz P, Wada Y, Ashikov A, Pérez-Cerdá C, Medrano C, Arnoldy A, Hoischen A, Huijben K, Steenbergen G, Quelhas D, Diogo L, Rymen D, Jaeken J, Guffon N, et al.

Am J Hum Genet. 2016 Feb 4;98(2):310-21. doi: 10.1016/j.ajhg.2015.12.010. Epub 2016 Jan 28.

PubMed [citation]

PMID:: 26833332
PMCID:: PMC4746332

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000264366.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001528294.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001653114.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	1	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005085896.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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