ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Published functional studies demonstrate no significant impact on expression, secretion, hemolytic activity or other functional properties (Mohlin et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23847193, 30131807, 29888403, 24029428, 24736606, 28852487, 28911789, 27939104, 27013439, 26638553)

C3 NM_000064.3 exon 41 p.Ser1619Arg (c.4855A>C): This variant has been reported in the literature in at least 1 individual with atypical hemolytic uremic syndrome (aHUS) (Feng 2013 PMID:23847193, Bu 2014 PMID:24029428) as well as recurrent pregnancy loss (Mohlin 2018 PMID:30131807). This variant has also been reported in individuals with age-related macular degeneration; however, at least 1 of these publications suggest that this variant may not be associated with this presentation (Duvvari 2014 PMID:24736606, Geerlings 2018 PMID:29888403). This variant is present in 0.2% (278/129150) of European alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-6678030-T-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:330271). This variant amino acid Arginine (Arg) is present in 4 species (Squirrel, Pika, Ferret, Cavefish) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Variant summary: C3 c.4855A>C (p.Ser1619Arg) results in a non-conservative amino acid change located in the Netrin domain (IPR001134) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 1613968 control chromosomes, predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. c.4855A>C has been reported in the literature in individuals affected with Hemolytic Uremic Syndrome (Bu_2014, Feng_2013), Glomerulopathy (Haydock_2022) and recurrent pregnancy loss (Mohlin_2018) without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hemolytic Uremic Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Mohlin_2018). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 24029428, 23847193, 34714369, 30131807). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014and classified as benign/likely benign (n=5) and VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.

C3: BP4

The C3 c.4855A>C variant is predicted to result in the amino acid substitution p.Ser1619Arg. This variant has been reported in individuals in the heterozygous state, and along with the CFH c.3583G>T (p.Glu1195X) variant, with atypical hemolytic uremic syndrome (Supplemental Table 2, Patient 11, Bu et al. 2013. PubMed ID: 24029428; Patient ID MA-7, Feng et al. 2013. PubMed ID: 23847193; Dowen et al. 2017. PubMed ID: 28852487; Table S3, Geerlings et al. 2018. PubMed ID: 29888403; Huerta et al. 2018. PubMed ID: 28911789). This variant has also been reported in the heterozygous state in individuals with age-related macular degeneration (AMD) (Duvvari et al. 2014. PubMed ID: 24736606; Huerta et al. 2018. PubMed ID: 28911789, Table S3, Geerlings et al. 2018. PubMed ID: 29888403) and in an individual with spontaneous pregnancy loss (Mohlin et al. 2018. PubMed ID: 30131807). Of note, this variant was also reported in control populations (Duvvari et al. 2014. PubMed ID: 24736606; Huerta et al. 2018. PubMed ID: 28911789; Mohlin et al. 2018. PubMed ID: 30131807). This variant is reported in 0.22% of alleles in individuals, including one homozygote, of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding it pathogenicity in ClinVar, ranging from uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/330271/). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.