12-7086423-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM1PM2PM5PP5_Moderate

The NM_001733.7(C1R):​c.1073G>T​(p.Cys358Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C358Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

C1R
NM_001733.7 missense

Scores

1
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 6.05
Variant links:
Genes affected
C1R (HGNC:1246): (complement C1r) This gene encodes a member of the peptidase S1 protein family. The encoded protein is a proteolytic subunit in the complement system C1 complex. The complement system acts as a mediator in the innate immune response by ultimately triggering phagocytosis, inflammation, and rupturing the bacterial cell wall. Mutations in this gene are associated with Ehlers-Danlos Syndrome. [provided by RefSeq, Dec 2018]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS1
Transcript NM_001733.7 (C1R) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a disulfide_bond (size 49) in uniprot entity C1R_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001733.7
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-7086423-C-T is described in Lovd as [Pathogenic].
PP5
Variant 12-7086423-C-A is Pathogenic according to our data. Variant chr12-7086423-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 267351.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-7086423-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
C1RNM_001733.7 linkc.1073G>T p.Cys358Phe missense_variant 8/11 ENST00000647956.2 NP_001724.4 P00736
C1RNM_001354346.2 linkc.1115G>T p.Cys372Phe missense_variant 8/11 NP_001341275.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
C1RENST00000647956.2 linkc.1073G>T p.Cys358Phe missense_variant 8/11 NM_001733.7 ENSP00000497341.1 A0A3B3ISR2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
0
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:2
Pathogenic, criteria provided, single submitterresearchInstitute of Human Genetics, Medical University InnsbruckAug 23, 2016- -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 31, 2016- -
Ehlers-Danlos syndrome, periodontal type 2 Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of WashingtonOct 13, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
CADD
Uncertain
25
DEOGEN2
Benign
0.071
.;.;T;T;.
LIST_S2
Uncertain
0.89
D;.;D;D;D
MetaRNN
Uncertain
0.71
D;D;D;D;D
Sift4G
Uncertain
0.012
.;.;D;.;.
Vest4
0.80, 0.80, 0.79
gMVP
0.80

Splicing

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.

Other links and lift over

dbSNP: rs1057518645; hg19: -; API