Submissions for variant NM_000065.5(C6):c.2381+2T>C

gnomAD frequency: 0.00242  dbSNP: rs76202909

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422743	SCV000516180	likely pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	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 (PMID: 7535801, 24378253); 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: 22344438, 31453292, 31589614, 34426522, 36199823, 7535801, 31345219, 24378253)
Blueprint Genetics	RCV000422743	SCV000927277	pathogenic	not provided	2017-06-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002244875	SCV002048575	likely pathogenic	Complement component 6 deficiency	2023-11-02	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000422743	SCV002295220	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV002244875	SCV002515831	pathogenic	Complement component 6 deficiency	2022-04-28	criteria provided, single submitter	research	ACMG codes: PVS1, PS3, PS4_supporting, PM2_supporting, PP1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268046	SCV002550458	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV002244875	SCV004030256	likely pathogenic	Complement component 6 deficiency	2023-08-28	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV002244875	SCV004175762	pathogenic	Complement component 6 deficiency	2023-03-01	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV002244875	SCV004807393	likely pathogenic	Complement component 6 deficiency	2024-03-26	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002244875	SCV005086843	pathogenic	Complement component 6 deficiency	2023-07-17	criteria provided, single submitter	clinical testing	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 C6 deficiency (MIM#612446) and combined C6/C7 deficiency. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (341 heterozygotes, 1 homozygote). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported twice as a VUS, but many times as pathogenic and likely pathogenic (ClinVar). It is known as the C6PD allele, and was observed in multiple heterozygous, compound heterozygous or homozygous individuals with a subtotal or total C6 deficiency. It was also found in a heterozygous individual with an infection of the central nervous system, who had an additional heterozygous variant (p.(Arg521Ser)) in the C7 gene (PMID: 24378253, PMID: 7535801, PMID: 31440263, PMID: 33386334). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV002221153	SCV000033138	pathogenic	C6 deficiency, subtotal	1996-10-15	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000422743	SCV001548945	likely pathogenic	not provided		no assertion criteria provided	clinical testing	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000422743	SCV001740271	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000422743	SCV001930499	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000422743	SCV001958729	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000422743	SCV001968499	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409589	SCV004112324	likely pathogenic	C6-related disorder	2024-08-27	no assertion criteria provided	clinical testing	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 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.