Submissions for variant NM_012082.4(ZFPM2):c.121C>G (p.Pro41Ala)

gnomAD frequency: 0.00015  dbSNP: rs199535268

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001370583	SCV001567102	uncertain significance	46,XY sex reversal 9	2021-04-14	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ZFPM2-related conditions. This variant is present in population databases (rs199535268, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces proline with alanine at codon 41 of the ZFPM2 protein (p.Pro41Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine.
GeneDx	RCV001573859	SCV002013098	uncertain significance	not provided	2019-12-03	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002548644	SCV003543910	uncertain significance	Inborn genetic diseases	2022-09-26	criteria provided, single submitter	clinical testing	The c.121C>G (p.P41A) alteration is located in exon 2 (coding exon 2) of the ZFPM2 gene. This alteration results from a C to G substitution at nucleotide position 121, causing the proline (P) at amino acid position 41 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001573859	SCV003826114	uncertain significance	not provided	2020-02-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001573859	SCV004158335	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	ZFPM2: BP4
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573859	SCV001800324	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001573859	SCV001954303	likely benign	not provided		no assertion criteria provided	clinical testing