NM_001466.4(FZD2):c.1644G>A (p.Trp548Ter) AND Autosomal dominant omodysplasia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 2, 2022
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:: RCV000754771.2

Allele description [Variation Report for NM_001466.4(FZD2):c.1644G>A (p.Trp548Ter)]

NM_001466.4(FZD2):c.1644G>A (p.Trp548Ter)

Gene:

FZD2:frizzled class receptor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_001466.4(FZD2):c.1644G>A (p.Trp548Ter)

HGVS:

NC_000017.11:g.44559332G>A
NM_001466.4:c.1644G>AMANE SELECT
NP_001457.1:p.Trp548Ter
NC_000017.10:g.42636700G>A
NM_001466.3:c.1644G>A

Protein change:

W548*; TRP548TER

Links:

OMIM: 600667.0001; dbSNP: rs1568105666

NCBI 1000 Genomes Browser:

rs1568105666

Condition(s)

Name:: Autosomal dominant omodysplasia
Synonyms:: Omodysplasia 2
Identifiers:: MONDO: MONDO:0008123; MedGen: C2750355; Orphanet: 2733; OMIM: 164745

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000882661	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2019)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002769086	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25759469, 30455931, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000882661

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2019)

germline

literature only

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

SCV002769086

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 2, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

A mutation in FRIZZLED2 impairs Wnt signaling and causes autosomal dominant omodysplasia.

Saal HM, Prows CA, Guerreiro I, Donlin M, Knudson L, Sund KL, Chang CF, Brugmann SA, Stottmann RW.

Hum Mol Genet. 2015 Jun 15;24(12):3399-409. doi: 10.1093/hmg/ddv088. Epub 2015 Mar 10.

PubMed [citation]

PMID:: 25759469
PMCID:: PMC4834928

Warren HE, Louie RJ, Friez MJ, Frías JL, Leroy JG, Spranger JW, Skinner SA, Champaigne NL.

Clin Case Rep. 2018 Nov;6(11):2252-2255. doi: 10.1002/ccr3.1818.

PubMed [citation]

PMID:: 30455931
PMCID:: PMC6230601

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000882661.1

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

Description

In a mother and daughter with omodysplasia (OMOD2; 164745), Saal et al. (2015) identified heterozygosity for a c.1644G-A transition in the FZD2 gene, resulting in a trp548-to-ter (W548X) substitution at the periphery of the canonical DISHEVELLED (see DVL1, 601365) interaction domain. The mutation arose de novo in the mother, as it was not found in her unaffected parents; it was also not found in an in-house database, or in the NHLBI ESP6500 or 1000 Genomes Projects databases. Functional analysis in HEK293T cells showed a significant reduction in colocalization of DVL and FZD2 with the mutant compared to wildtype FZD2. In contrast to a 3-fold increase in WNT (see 164820) signaling with wildtype FZD2, the W548X mutant showed no observable increase in WNT activity over that of background levels.

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769086.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with omodysplasia 2 (MIM#164745). However, dominant negative has not been excluded as the mechanism of disease (PMID: 25759469). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated Frizzled family membrane region (DECIPHER). (SP) 0705 - No comparable downstream truncating variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been seen in three individuals with omodysplasia, including in one confirmed de novo case where the variant also segregates in the proband's affected daughter (ClinVar, PMID: 25759469, 30455931). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis in HEK293T cells showed variant FZD2 protein had significantly reduced colocalization with DVL. Variant FZD2 protein also showed no notable increase in WNT activity over background levels compared to a 3-fold increase with wild type FZD2 (PMID: 25759469). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

Last Updated: Sep 1, 2024

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