rs1057519577

chr12-7088636-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Moderate PM1 PP3_Strong PP5_Very_Strong

The NM_001733.7(C1R):c.1012T>C(p.Cys338Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 9/14 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.57

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 Pathogenic. Variant got 16 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 domain Sushi 1 (size 66) in uniprot entity C1R_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_001733.7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 12-7088636-A-G is Pathogenic according to our data. Variant chr12-7088636-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 375578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1R	NM_001733.7	c.1012T>C	p.Cys338Arg	missense_variant	7/11	ENST00000647956.2
C1R	NM_001354346.2	c.1054T>C	p.Cys352Arg	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1R	ENST00000647956.2	c.1012T>C	p.Cys338Arg	missense_variant	7/11		NM_001733.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, Medical University Innsbruck	Aug 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 28, 2023	PS3 PM2 PM1 PS4_Supporting PP3 Path -

Ehlers-Danlos syndrome, periodontal type 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Oct 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;.;T;T;T
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.79	T
Polyphen		1.0	.;.;D;D;.
Vest4		0.97, 0.96, 0.96
MutPred		0.97		Loss of methylation at K339 (P = 0.0163);Loss of methylation at K339 (P = 0.0163);.;.;.;
MVP		0.61
ClinPred		1.0	D
GERP RS		5.8
gMVP		0.92

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519577; hg19: chr12-7241232;