Submissions for variant NM_016335.6(PRODH):c.1357C>T (p.Arg453Cys) (rs3970559)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000454992	SCV000540120	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 3% in African population, >1% in most other populations. In addition, no clearly associated clinical manifestations
Invitae	RCV000004214	SCV000631842	uncertain significance	Proline dehydrogenase deficiency	2019-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 453 of the PRODH protein (p.Arg453Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs3970559, ExAC 3%). This variant has previously been reported as a susceptibility allele for hyperprolinemia (PMID: 15494707, 22090377, 24842239). However, this assertion was based on a small study size and other causes of clinical symptoms were not ruled out. ClinVar contains an entry for this variant (Variation ID: 4006). Experimental studies have shown that this missense change reduces POX1 activity (PMID: 15662599). In summary, this variant is a missense change that has been described as a risk factor for hyperprolinemia and has been shown to affect protein function. However, it is very common in the population. For these reasons, it has been classified as a Variant of Uncertain Significance.
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital	RCV000454992	SCV000864289	likely benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing	BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).
OMIM	RCV000004214	SCV000024380	pathogenic	Proline dehydrogenase deficiency	2005-03-01	no assertion criteria provided	literature only
OMIM	RCV000004215	SCV000024381	risk factor	Schizophrenia 4	2005-03-01	no assertion criteria provided	literature only

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