Submissions for variant NM_000063.6(C2):c.841_849+19del

dbSNP: rs9332736

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169652	SCV000221177	pathogenic	Complement component 2 deficiency	2017-01-12	criteria provided, single submitter	clinical testing	The c.841_849+19del variant in C2 is the most common pathogenic variant for C2 deficiency (Johnson 1992, Truedsson 1993), accounting for about 90% of cases (Truedsson 2015). It has been identified in 1.2% (123/10162) of Ashkenazi Jewish chromosomes and 0.8% (1001/126816) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs572361305); however, this frequency is low enough to be consistent with the frequency of C2 deficiency in the general population. This variant is a deletion of 28 bp, including the invariant region of the splice consensus sequence, and has been shown to cause skipping of exon 6, leading to a frameshift (Johnson 1992). In summary, the c.841_849+19del meets criteria to be classified as pathogenic for C2 deficiency in an autosomal recessive manner.
Blueprint Genetics	RCV000788701	SCV000927903	pathogenic	not provided	2018-08-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000788701	SCV001246060	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	C2: PM3:Very Strong, PVS1, PM2:Supporting, PS3:Supporting
Invitae	RCV000788701	SCV001589360	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 6 (c.841_849+19del) of the C2 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs572361305, gnomAD 1.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with C2 deficiency (PMID: 1577763, 9616367, 31440263). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 50634). Studies have shown that this variant results in skipping of exon 6 and introduces a premature termination codon (PMID: 1577763). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000788701	SCV001766808	pathogenic	not provided	2022-01-06	criteria provided, single submitter	clinical testing	Functional studies demonstrate that this variant results in skipping of exon 6 (Johnson et al., 1992); 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; This variant is associated with the following publications: (PMID: 1577763, 31440263, 25454804, 33726816, 27535533)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000788701	SCV002010280	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000788701	SCV002502242	likely pathogenic	not provided	2022-03-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000169652	SCV002518620	pathogenic	Complement component 2 deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477141	SCV002800635	pathogenic	Complement component 2 deficiency; Age related macular degeneration 14	2022-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387742	SCV004099795	pathogenic	C2-related disorder	2023-09-13	criteria provided, single submitter	clinical testing	Variant summary: C2 c.841_849+19del28 involves the deletion of a canonical 5' donor splice-site and is therefore predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Accordingly, several computational tools predict a significant impact on normal splicing, with three predicting the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing, resulting in the skipping of exon 6, which causes a frameshift and premature termination codon that is expected to be affected by nonsense mediate decay. The variant allele was found at a frequency of 0.0046 in 251134 control chromosomes in the gnomAD database, including 2 homozygotes and is found at a high frequency (0.011) in the Ashkenazi Jewish subpopulation, providing supporting evidence for a benign role. However, c.841_849+19del28 has been reported in the literature in multiple homozygous individuals affected with Complement Component 2 Deficiency and has been found to segregate with the disease phenotype in more than one family (e.g. Johnson_1992, Rice_2016, Morup_2022). These data indicate that the variant is very likely to be associated with disease, but may exhibit reduced penetrance. The following publications have been ascertained in the context of this evaluation (PMID: 1577763, 27943079, 35874679). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=9)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000788701	SCV004243269	likely pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003387742	SCV004734783	likely pathogenic	C2-related disorder	2023-12-09	criteria provided, single submitter	clinical testing	The C2 c.841_849+19del28 variant is predicted to result in a deletion affecting a canonical splice site. This variant is predicted to result in a deletion encompassing the splice donor site at the exon 6/intron 6 boundary and has been reported to result in exon 6 skipping, with splicing prediction programs also indicating splicing alterations (Johnson et al. 1992. PubMed ID: 1577763; Alamut Visual Plus v1.6.1). This variant has been reported in many homozygous and compound heterozygous individuals with complement C2 deficiency (Zhu et al. 1998. PubMed ID: 9670930; Johnson et al. 1992. PubMed ID: 1577763; Liphaus et al. 2015. PubMed ID: 26017655; Blazina et al. 2018. PubMed ID: 29619023). Of note, heterozygous carriers of the c.841_849+19del were also found to have clinical features of C2 deficiency, including purulent meningitis, recurrent sinusitis, recurrent impetigo, pneumonia, and recurrent otitis (Blazina et al. 2018. PubMed ID: 29619023). This variant is reported in 1.18% of alleles in individuals of Ashkenazi Jewish descent in gnomAD; however, the allele balance is skewed for many heterozygous individuals indicating this data may not be reliable. In the ClinVar database, this variant has been reported as pathogenic or likely pathogenic by several outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/50634/). Of note, alternative transcripts have been reported for the C2 gene including two which have alternative splicing omitting exon 6 (NM_001178063.2 and NM_001282457.1; Cheng and Volanakis. 1994. PubMed ID: 8120386). Taken together, we interpret this variant as likely pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000169652	SCV004810066	uncertain significance	Complement component 2 deficiency	2024-04-04	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000788701	SCV005196898	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV002264641	SCV000033151	pathogenic	C2 deficiency, type I	1992-05-05	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000169652	SCV001142353	pathogenic	Complement component 2 deficiency	2020-01-06	no assertion criteria provided	curation	NM_001282459.1:c.841_868del in the C2 gene has an allele frequency of 0.012 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant also known as NM_000063.6(C2):c.841_849+19del has been reported in homozygosity in 6 probands with C2-deficiency, and segregated with disease in 2 affected homozygous relatives in one family (PMID: 1577763). The 28bp deletion leads to skipping of exon 6 and a premature stop-codon. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM3, PP4, PP1.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000169652	SCV001192657	pathogenic	Complement component 2 deficiency	2019-11-19	no assertion criteria provided	clinical testing