Variant chr12-7086423-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP5_Moderate

The NM_001733.7(C1R):c.1073G>A(p.Cys358Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C358F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

C1R
NM_001733.7 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

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]

C1R links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

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 chrnull-null-null-null is described in UniProt as null.

PP5

Variant 12-7086423-C-T is Pathogenic according to our data. Variant chr12-7086423-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2444516.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-7086423-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1R	NM_001733.7 link	c.1073G>A	p.Cys358Tyr	missense_variant	8/11	ENST00000647956.2	NP_001724.4	P00736
C1R	NM_001354346.2 link	c.1115G>A	p.Cys372Tyr	missense_variant	8/11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2 link	c.1073G>A	p.Cys358Tyr	missense_variant	8/11		NM_001733.7	ENSP00000497341.1		A0A3B3ISR2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

246412

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

124888

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Jan 27, 2023

We observed a c.1073G>A (p.Cys358Tyr) genetic variant in heterozygous state in the C1R gene in proband (male, 34 y.o.) and his son (5 y.o.) with Ehlers-Danlos syndrome, periodontal type, 1 (MIM number 130080). This variant is not present in databases (gnomAD, LOVD). ClinVar contains an entry for this variant (Variation ID: 267351) observed in patients with the consistent phenotype. Mutations in the C1R gene are known to be pathogenic (PMID: 27745832, 35365885), including the alternative variant p.Cys358Phe in the same codon. We assume that the c.1073G>A (p.Cys358Tyr) variant could be classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CADD

Uncertain

DEOGEN2

Benign

0.30

.;.;T;T;.

LIST_S2

Uncertain

0.91

D;.;D;D;D

MetaRNN

Uncertain

0.71

D;D;D;D;D

Sift4G

Uncertain

0.0030

.;.;D;.;.

Vest4

0.85, 0.85, 0.83

gMVP

0.85

Splicing

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over