NM_001386094.1(AGBL1):c.3044G>C (p.Cys1015Ser) AND Corneal dystrophy, Fuchs endothelial, 8

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 20, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000074409.6

Allele description [Variation Report for NM_001386094.1(AGBL1):c.3044G>C (p.Cys1015Ser)]

NM_001386094.1(AGBL1):c.3044G>C (p.Cys1015Ser)

Gene:

AGBL1:AGBL carboxypeptidase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q25.3

Genomic location:

Preferred name:

NM_001386094.1(AGBL1):c.3044G>C (p.Cys1015Ser)

Other names:

C990S

HGVS:

NC_000015.10:g.86674322G>C
NG_033836.2:g.599515G>C
NM_001386094.1:c.3044G>CMANE SELECT
NM_152336.4:c.3107G>C
NP_001373023.1:p.Cys1015Ser
NP_689549.3:p.Cys1036Ser
NC_000015.9:g.87217553G>C
NM_152336.2:c.2969G>C
Q96MI9:p.Cys990Ser

Protein change:

C1015S; CYS990SER

Links:

UniProtKB: Q96MI9#VAR_070225; OMIM: 615496.0002; dbSNP: rs181958589

NCBI 1000 Genomes Browser:

rs181958589

Molecular consequence:

NM_001386094.1:c.3044G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_152336.4:c.3107G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Corneal dystrophy, Fuchs endothelial, 8 (FECD8)
Identifiers:: MONDO: MONDO:0014228; MedGen: C3809798; Orphanet: 98974; OMIM: 615523

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106021	OMIM	no assertion criteria provided	Pathogenic (Oct 3, 2013)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002517529	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV004014852	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 20, 2023)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000106021

OMIM

no assertion criteria provided

Pathogenic
(Oct 3, 2013)

germline

literature only

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

SCV002517529

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2019)

Pathogenic
(May 4, 2022)

germline

clinical testing

Citation Link,

SCV004014852

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jul 20, 2023)

paternal

clinical testing

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	paternal	no	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4.

Riazuddin SA, Vasanth S, Katsanis N, Gottsch JD.

Am J Hum Genet. 2013 Oct 3;93(4):758-64. doi: 10.1016/j.ajhg.2013.08.010.

PubMed [citation]

PMID:: 24094747
PMCID:: PMC3791265

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000106021.1

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

Description

In 3 unrelated probands with Fuchs corneal dystrophy (FECD8; 615523), Riazuddin et al. (2013) identified heterozygosity for a c.2969G-C transition in the AGBL1 gene, resulting in a cys990-to-ser (C990S) substitution at a completely conserved residue. The missense variant was not found in 384 ethnically matched controls, but was present in the NHLBI Exome Variant Server at a low MAF of 0.0025 in the European American population. Transfection studies in HEK293 cells showed a relative decrease in AGBL1 with the C990S mutant compared to wildtype, and immunoprecipitation of the mutant allele showed significantly reduced binding to TCF4 (602272) compared to wildtype.

#	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

From Mendelics, SCV002517529.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Intergen, Intergen Genetics and Rare Diseases Diagnosis Center, SCV004014852.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	no	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Feb 4, 2024

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