Submissions for variant NM_004924.6(ACTN4):c.1279G>A (p.Ala427Thr)

gnomAD frequency: 0.00029  dbSNP: rs201128110

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV000735721	SCV001428606	uncertain significance	Focal segmental glomerulosclerosis 1	2017-03-29	criteria provided, single submitter	clinical testing
GeneDx	RCV002225721	SCV002504439	likely benign	not provided	2021-02-16	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294377	SCV002587237	uncertain significance	Focal segmental glomerulosclerosis	2022-07-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002225721	SCV003288192	uncertain significance	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 427 of the ACTN4 protein (p.Ala427Thr). This variant is present in population databases (rs201128110, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with focal segmental glomerulosclerosis (PMID: 16251236, 23890478, 29869118, 31027891). ClinVar contains an entry for this variant (Variation ID: 599123). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTN4 protein function with a negative predictive value of 80%. 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.
CeGaT Center for Human Genetics Tuebingen	RCV002225721	SCV004141655	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	ACTN4: BP4, BS2
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000735721	SCV000863874	uncertain significance	Focal segmental glomerulosclerosis 1	2018-05-17	no assertion criteria provided	clinical testing