NM_001733.7(C1R):c.149_150delinsAT (p.Val50Asp) AND Ehlers-Danlos syndrome, periodontal type 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 23, 2016
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000412647.3

Allele description [Variation Report for NM_001733.7(C1R):c.149_150delinsAT (p.Val50Asp)]

NM_001733.7(C1R):c.149_150delinsAT (p.Val50Asp)

Gene:

C1R:complement C1r [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

12p13.31

Genomic location:

Preferred name:

NM_001733.7(C1R):c.149_150delinsAT (p.Val50Asp)

Other names:

C1R, VAL32ASP; V32D

HGVS:

NC_000012.12:g.7091533_7091534delinsAT
NG_062465.1:g.6074_6075delinsAT
NM_001354346.2:c.191_192delinsAT
NM_001733.7:c.149_150delinsATMANE SELECT
NP_001341275.1:p.Val64Asp
NP_001724.4:p.Val50Asp
LRG_1321t1:c.149_150delinsAT
LRG_1321:g.6074_6075delinsAT
LRG_1321p1:p.Val50Asp
NC_000012.11:g.7244129_7244130delinsAT
NM_001733.4:c.149_150TC>AT
NM_001733.4:c.149_150TC>AT
NM_001733.6:c.149_150delinsAT

Protein change:

V50D; VAL32ASP

Links:

OMIM: 613785.0001; dbSNP: rs1057519025

NCBI 1000 Genomes Browser:

rs1057519025

Molecular consequence:

NM_001354346.2:c.191_192delinsAT - missense variant - [Sequence Ontology: SO:0001583]
NM_001733.7:c.149_150delinsAT - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

variation affecting protein function [Variation Ontology: 0003]

Condition(s)

Name:: Ehlers-Danlos syndrome, periodontal type 1
Identifiers:: MONDO: MONDO:0020684; MedGen: C4551499; Orphanet: 75392; OMIM: 130080

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000297990	Institute of Human Genetics, Medical University Innsbruck	criteria provided, single submitter (Kapferer-Seebacher et al. (Am J Hum Genet. 2016))	Pathogenic (Aug 23, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000328234	OMIM	no assertion criteria provided	Pathogenic (Oct 31, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000297990

Institute of Human Genetics, Medical University Innsbruck

criteria provided, single submitter

(Kapferer-Seebacher et al. (Am J Hum Genet. 2016))

Pathogenic
(Aug 23, 2016)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV000328234

OMIM

no assertion criteria provided

Pathogenic
(Oct 31, 2016)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.

Kapferer-Seebacher I, Pepin M, Werner R, Aitman TJ, Nordgren A, Stoiber H, Thielens N, Gaboriaud C, Amberger A, Schossig A, Gruber R, Giunta C, Bamshad M, Björck E, Chen C, Chitayat D, Dorschner M, Schmitt-Egenolf M, Hale CJ, Hanna D, Hennies HC, Heiss-Kisielewsky I, et al.

Am J Hum Genet. 2016 Nov 3;99(5):1005-1014. doi: 10.1016/j.ajhg.2016.08.019. Epub 2016 Oct 13.

PubMed [citation]

PMID:: 27745832
PMCID:: PMC5097948

Details of each submission

From Institute of Human Genetics, Medical University Innsbruck, SCV000297990.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From OMIM, SCV000328234.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a large 5-generation Austrian family (family 1) with the periodontal type of Ehlers-Danlos syndrome (EDSPD1; 130080), Kapferer-Seebacher et al. (2016) identified heterozygosity for a c.149_150TC-AT change (c.149_150TC-AT, NM_001733.4) in the C1R gene, resulting in a val50-to-asp substitution (val32-to-asp (V32D) in the mature protein) at an evolutionarily conserved residue within the CUB1 collagen-binding domain. The mutation segregated fully with disease in the family, and was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases. Western blots of HEK293 cells and supernatants in which V50D had been overexpressed indicated that the abnormal C1R protein was retained in the cell but could undergo autoactivation that might lead to interaction with off-target substrates. In addition, mutation-transfected cells showed an increased proportion of dilated cisternae of the rough endoplasmic reticulum compared to controls. Kapferer-Seebacher et al. (2016) noted that unlike previously reported families with EDSPD, none of the affected individuals in this family exhibited pretibial discoloration.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 11, 2023

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