5-40959520-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -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).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 15 hom. )

Consequence

C7
NM_000587.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:5

Conservation

PhyloP100: 0.470

Variant links:

Genes affected

C7 (HGNC:1346): (complement C7) This gene encodes a serum glycoprotein that forms a membrane attack complex together with complement components C5b, C6, C8, and C9 as part of the terminal complement pathway of the innate immune system. The protein encoded by this gene contains a cholesterol-dependent cytolysin/membrane attack complex/perforin-like (CDC/MACPF) domain and belongs to a large family of structurally related molecules that form pores involved in host immunity and bacterial pathogenesis. This protein initiates membrane attack complex formation by binding the C5b-C6 subcomplex and inserts into the phospholipid bilayer, serving as a membrane anchor. Mutations in this gene are associated with a rare disorder called C7 deficiency. [provided by RefSeq, Nov 2016]

C7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP5

Variant 5-40959520-C-A is Pathogenic according to our data. Variant chr5-40959520-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12105.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4, Pathogenic=6}. Variant chr5-40959520-C-A is described in UniProt as null. Variant chr5-40959520-C-A is described in Lovd as [Likely_pathogenic]. Variant chr5-40959520-C-A is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C7	NM_000587.4 link	c.1561C>A	p.Arg521Ser	missense_variant	Exon 12 of 18	ENST00000313164.10	NP_000578.2	P10643Q05CI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C7	ENST00000313164.10 link	c.1561C>A	p.Arg521Ser	missense_variant	Exon 12 of 18	1	NM_000587.4	ENSP00000322061.9		P10643

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.000944

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00434

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00233

AC:

574

AN:

246854

Hom.:

AF XY:

0.00238

AC XY:

319

AN XY:

133880

show subpopulations

Gnomad AFR exome

AF:

0.000525

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000891

Gnomad FIN exome

AF:

0.000606

Gnomad NFE exome

AF:

0.00421

Gnomad OTH exome

AF:

0.00334

GnomAD4 exome

AF:

0.00318

AC:

4640

AN:

1459306

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

2266

AN XY:

725784

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00137

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00134

Gnomad4 FIN exome

AF:

0.00103

Gnomad4 NFE exome

AF:

0.00381

Gnomad4 OTH exome

AF:

0.00254

GnomAD4 genome

AF:

0.00248

AC:

378

AN:

152206

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.000944

Gnomad4 NFE

AF:

0.00434

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00372

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00388

AC:

ExAC

AF:

0.00247

AC:

298

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Complement component 7 deficiency

Pathogenic:9Uncertain:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 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 -

Jun 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 03, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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] -

Apr 28, 2022

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes: PS3, PS4_supporting, PM2_supporting, PP1 -

Aug 28, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 08, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2Uncertain:2

Jan 13, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 02, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

C7 and C6 deficiency, combined subtotal

Pathogenic:1

Jun 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

C7-related disorder

Uncertain:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.14

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.58

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

5.0

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MVP

0.72

MPC

0.14

ClinPred

0.15

GERP RS

4.3

Varity_R

0.98

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over