NM_003659.4(AGPS):c.1037_1043del (p.Glu346fs) AND Rhizomelic chondrodysplasia punctata type 3

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 20, 2020
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:: RCV001449736.5

Allele description [Variation Report for NM_003659.4(AGPS):c.1037_1043del (p.Glu346fs)]

NM_003659.4(AGPS):c.1037_1043del (p.Glu346fs)

Gene:

AGPS:alkylglycerone phosphate synthase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_003659.4(AGPS):c.1037_1043del (p.Glu346fs)

HGVS:

NC_000002.12:g.177468456_177468462del
NG_008968.1:g.80714_80720del
NM_003659.4:c.1037_1043delMANE SELECT
NP_003650.1:p.Glu346fs
NC_000002.11:g.178333184_178333190del
NC_000002.11:g.178333184_178333190delAAAAAAG

Protein change:

E346fs

Links:

dbSNP: rs2105675391

NCBI 1000 Genomes Browser:

rs2105675391

Molecular consequence:

NM_003659.4:c.1037_1043del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Rhizomelic chondrodysplasia punctata type 3 (RCDP3)
Synonyms:: Alkyldihydroxyacetonephosphate synthase deficiency; Alkylglycerone Phosphate Synthase (AGPS) deficiency
Identifiers:: MONDO: MONDO:0010823; MedGen: C1838612; Orphanet: 177; OMIM: 600121

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001653007	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Apr 20, 2020)	germline	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

SCV001653007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Apr 20, 2020)

germline

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	unknown	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001653007.1

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

Description

The p.Glu346AlafsX26 variant in AGPS has not been previously reported in individuals with rhizomelic chondrodysplasia punctata and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 346 and leads to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Although most of the AGPS variants reported in patients with rhizomelic chondrodysplasia punctata have been missense changes, in vitro and in vivo functional studies and population data are supportive of a loss of function mechanism of disease (Itzkovitz 2012, Liegel 2014, http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive rhizomelic chondrodysplasia punctata. ACMG/AMP Criteria applied: PVS1_Strong, PM2.

#	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		1	not provided	1	not provided

Last Updated: Jun 23, 2024

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