12-7086423-C-T

Variant names:

• chr12-7086423-C-T
• NM_001733.7:c.1073G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.05

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Sushi 1 (size 66) in uniprot entity C1R_HUMAN there are 10 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 rank	MANE	Protein	UniProt
C1R	NM_001733.7	c.1073G>A	p.Cys358Tyr	missense_variant	Exon 8 of 11	ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.1115G>A	p.Cys372Tyr	missense_variant	Exon 8 of 11		NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.1073G>A	p.Cys358Tyr	missense_variant	Exon 8 of 11		NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 246412 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:1

Jan 27, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	25
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.

Other links and lift over

hg19: -;