rs121964920
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP5BS2
The NM_000587.4(C7):c.1561C>A(p.Arg521Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,611,512 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000587.4 missense
Scores
Clinical Significance
Conservation
Publications
- complement component 7 deficiencyInheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000587.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| C7 | NM_000587.4 | MANE Select | c.1561C>A | p.Arg521Ser | missense | Exon 12 of 18 | NP_000578.2 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| C7 | ENST00000313164.10 | TSL:1 MANE Select | c.1561C>A | p.Arg521Ser | missense | Exon 12 of 18 | ENSP00000322061.9 | ||
| C7 | ENST00000696333.1 | c.1561C>A | p.Arg521Ser | missense | Exon 12 of 18 | ENSP00000512566.1 | |||
| C7 | ENST00000696441.1 | c.1561C>A | p.Arg521Ser | missense | Exon 12 of 17 | ENSP00000512631.1 |
Frequencies
GnomAD3 genomes 0.00248 AC: 377AN: 152088Hom.: 1 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00233 AC: 574AN: 246854 AF XY: 0.00238 show subpopulations
GnomAD4 exome AF: 0.00318 AC: 4640AN: 1459306Hom.: 15 Cov.: 31 AF XY: 0.00312 AC XY: 2266AN XY: 725784 show subpopulations
Age Distribution
GnomAD4 genome 0.00248 AC: 378AN: 152206Hom.: 1 Cov.: 32 AF XY: 0.00238 AC XY: 177AN XY: 74402 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Complement component 7 deficiency Pathogenic:10Uncertain:1
ACMG codes: PS3, PS4_supporting, PM2_supporting, PP1
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 C7 deficiency (MIM#610102). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (653 heterozygotes, 1 homozygote). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 32 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated thrombospondin type 1 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS, but more commonly as likely pathogenic or pathogenic (ClinVar). It is known as the C7PD allele, and was observed in multiple heterozygous, compound heterozygous or homozygous individuals with a subtotal or total C7 deficiency. It was also found in a heterozygous individual with an infection of the central nervous system, who had an additional heterozygous variant (c.2381+2T>C) in the C6 gene (PMID: 17407100, PMID: 31440263, PMID: 33386334). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been proven to result in protein mislocalization into the endoplasmic reticulum, with significantly reduced secretion (PMID: 17407100). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
The observed missense c.1561C>A p.Arg521Ser variant in C7 gene has been observed in individuals with complement component 7 C7 deficiency Fernie et al., 1996; Barroso et al., 2006; Rameix-Welti et al., 2007; Kuijpers et al., 2010. Experimental studies have shown that this missense change affects C7 function Rameix-Welti et al., 2007 The p.Arg521Ser variant is present with allele frequency of 0.2% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance/ Likely Pathogenic/ Pathogenic multiple submissions. Multiple lines of computational evidence Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg521Ser in C7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 521 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. In absence of another reportable variant in C7 gene, the molecular diagnosis is not confirmed.
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 8871666] This variant has been previously reported in patients with complement component 7 deficiency [PMID 8871666, 16771861]
The C7 c.1561C>A; p.Arg521Ser variant (rs121964920) is reported in several individuals with C7 deficiency who also carried a truncating C7 variant (Barroso 2006, Sanges 2017). The variant is reported in the ClinVar database (Variation ID: 12105) and is found in the general population with an overall allele frequency of 0.2% (655/278,228 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.399). Based on available information, this variant is classified as likely pathogenic. References: Barroso S et al. Molecular defects of the C7 gene in two patients with complement C7 deficiency. Immunology. 2006 Jun;118(2):257-60. Sanges S et al. Diagnosis of primary antibody and complement deficiencies in young adults after a first invasive bacterial infection. Clin Microbiol Infect. 2017 Aug;23(8):576.e1-576.e5.
The p.Arg521Ser variant (also referred to as R499S in the literature) in the C7 gene has been previously reported in at least 4 unrelated individuals with features consistent with C7 deficiency (Barroso et al., 2006; Fernie et al., 1996; Rameix-Welti et al., 2007; Rosain et al., 2017). All individuals were homozygous or compound heterozygous. The p.Arg521Ser variant was determined to be in trans with a disease-associated variants (p.Gly379Arg; c.2350+2T>C; p.Cys464X), consistent with autosomal recessive inheritance. The presence of this variant with a disease-causing variant on the opposite allele increases suspicion for its pathogenicity. The p.Arg521Ser variant has also been identified in 526/127,222 European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency of C7 deficiency. Functional studies of this variant are supportive of a deleterious effect to the protein; however, it is unclear if this would be sufficient to be disease-causing (Rameix-Welti et al., 2007). Computational tools predict that this variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg521Ser variant as likely pathogenic for C7 deficiency in an autosomal recessive manner based on the information above. [ACMG evidence codes used: PS3_moderate; PM3_strong]
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.235%). Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. Premature termination of the protein is a common disease-causing mechanism for this gene. In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.78 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012105 /PMID: 8871666). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
not provided Pathogenic:2Uncertain:2
This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 521 of the C7 protein (p.Arg521Ser). This variant is present in population databases (rs121964920, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with complement component 7 (C7) deficiency (PMID: 8871666, 16771861, 17407100, 19931914). This variant is also known as R499S. ClinVar contains an entry for this variant (Variation ID: 12105). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt C7 protein function. Experimental studies have shown that this missense change affects C7 function (PMID: 17407100). 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.
Published functional studies demonstrate a loss of function of C7 due to the defective folding of the protein (PMID: 17407100); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R499S; This variant is associated with the following publications: (PMID: 28192236, 8871666, 31980526, 16771861, 17407100, 31440263, 31589614, 34573280, 34426522, 28368462, 35899558, 39081726, 39062917, 38096369)
C7 and C6 deficiency, combined subtotal Pathogenic:1
C7-related disorder Uncertain:1
The C7 c.1561C>A variant is predicted to result in the amino acid substitution p.Arg521Ser. This variant is alternatively referred to as p.Arg499Ser using Legacy nomenclature or as allele C7SD. This variant has been reported in the homozygous state in two unrelated individuals with combined complement component 6- (C6D) and complement component 7- (C7D) deficiency (referred to as C7 exon 11 mutation, Fig. 2, Family 1, Subject II.1 and Fig. 3, Family 2, Subject I.1, Fernie et al. 1996. PubMed ID: 8871666). Of note, one of these individuals was also homozygous for a splicing variant in the C6 gene. It has been reported in the heterozygous state along with a second truncating variant in C7 in individual with complement deficiencies (Fig. 1, Barroso et al. 2006. PubMed ID: 16771861; Sanges et al. 2017. PubMed ID: 28192236). This variant has been reported in the heterozygous state in two siblings with C7D (Fig. 7, Family 6, Subjects II.1 and 11.2, Fernie et al. 1996. PubMed ID: 8871666), in individuals with terminal complement pathway deficiency (Table S1, Rosain et al. 2017. PubMed ID: 28368462; Table 3, El Sissy et al. 2019. PubMed ID: 31440263), and in an individual with a inborn error of immunity (Table 1, Grossi et al. 2021. PubMed ID: 34573280). However, this variant has also been reported in the heterozygous state in individuals without C7D and is a common homozygous finding in the Turkish population (Fig. 2-4, 6, and 7, Fernie et al. 1996. PubMed ID: 8871666; Table S1, Capalbo et al. 2019. PubMed ID: 31589614; Hou et al. 2020. PubMed ID: 31980526; Table S4, Kars. 2021. PubMed ID: 34426522). This variant is reported in 0.41% of alleles in individuals of European (Non-Finnish) descent in gnomAD including one homozygous finding. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
not specified Uncertain:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at