Submissions for variant NM_012082.4(ZFPM2):c.89A>G (p.Glu30Gly)

gnomAD frequency: 0.00302  dbSNP: rs121908601

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461090	SCV000557284	likely benign	46,XY sex reversal 9	2025-01-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818141	SCV002071439	likely benign	not specified	2017-08-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001573801	SCV004032829	benign	not provided	2025-03-01	criteria provided, single submitter	clinical testing	ZFPM2: BP4, BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV001573801	SCV005224033	likely benign	not provided		criteria provided, single submitter	not provided
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818141	SCV005726620	benign	not specified	2024-11-19	criteria provided, single submitter	clinical testing	Variant summary: ZFPM2 c.89A>G (p.Glu30Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0042 in 1613668 control chromosomes in the gnomAD database, including 18 homozygotes. The variant allele was found at a frequency of 0.0042 in 1613668 control chromosomes, predominantly at a frequency of 0.0052 within the Non-Finnish European subpopulation in the gnomAD database, including 15 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2500-fold of the estimated maximal expected allele frequency for a pathogenic variant in ZFPM2 causing Tetralogy Of Fallot phenotype (2.1e-06), strongly suggesting the variant is a benign polymorphism. c.89A>G has been reported in the literature in control individuals and in individuals affected with Tetralogy Of Fallot or with atrioventricular septal defect, both without evidence of causality (e.g. D'Alessandro_2018, Pizzuti_2003, Priest_2016, Freudenberg-Hua_2014). These reports do not provide unequivocal conclusions about association of the variant with Tetralogy Of Fallot. At least one publication reports experimental evidence evaluating an impact on protein function, showing no damaging effect of this variant evidenced by maintained binding with and transcriptional activity of co-regulator of transcription, GATA4 (e.g. Pizzuti_2003). The following publications have been ascertained in the context of this evaluation (PMID: 25996639, 14517948, 27058611, 25333069). ClinVar contains an entry for this variant (Variation ID: 6128). Based on the evidence outlined above, the variant was classified as benign.
OMIM	RCV000006502	SCV000026685	pathogenic	Tetralogy of Fallot	2015-04-01	no assertion criteria provided	literature only
OMIM	RCV000032713	SCV000056477	pathogenic	Double outlet right ventricle	2015-04-01	no assertion criteria provided	literature only
OMIM	RCV000172841	SCV000223807	pathogenic	Diaphragmatic hernia 3	2015-04-01	no assertion criteria provided	literature only
Reproductive Development, Murdoch Childrens Research Institute	RCV001007696	SCV001146893	benign	46,XY sex reversal 3	2019-08-26	no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573801	SCV001800183	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001573801	SCV001931789	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924804	SCV004739158	likely benign	ZFPM2-related disorder	2021-08-16	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).