Submissions for variant NM_001615.4(ACTG2):c.533G>A (p.Arg178His)

dbSNP: rs587777384

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190653	SCV000244093	pathogenic	Inborn genetic diseases	2013-08-09	criteria provided, single submitter	clinical testing	The c.533G>A (p.R178H) alteration is located in coding exon 5 of the ACTG2 gene. This alteration results from a G to A substitution at nucleotide position 533. The arginine at codon 178 is replaced by histidine, an amino acid with highly similar properties.The missense change is not observed in healthy cohorts:Based on data from the NHLBI Exome Sequencing Project (ESP), the ACTG2 c.533G>A (p.R178H) alteration was not observed among 6,502 individuals tested (0.0%). Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP).The altered amino acid is highly conserved throughout evolution:The R178 amino acid is conserved throughout vertebrates as well as among all the six actin proteins in human.The alteration is predicted benign by in silico models:The p.R178H alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses.The alteration is de novo in the proband herein:Co-segregation analysis of the c.533G>A (p.R178H alteration in this family revealed that the unaffected mother and father do not carry this alteration, indicating a likely de novo mutation occurrence.Based on the available evidence, the ACTG2 c.533G>A (p.R178H) alteration is classified as a pathogenic mutation.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000119270	SCV000256737	pathogenic	Visceral myopathy 1	2014-03-27	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000119270	SCV000893620	pathogenic	Visceral myopathy 1	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV002460924	SCV002757760	pathogenic	not provided	2022-11-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on actin polymerization (Halim D et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26647307, 24676022, 32621347, 33859849, 25998219, 34071279, 32810037, 34980693)
OMIM	RCV001535394	SCV000154705	pathogenic	Megacystis-microcolon-intestinal hypoperistalsis syndrome 5	2014-03-01	no assertion criteria provided	literature only
UOSD Genetics and Genomics of Rare Diseases, Istituto Giannina Gaslini	RCV000119270	SCV000256210	pathogenic	Visceral myopathy 1	2015-05-02	no assertion criteria provided	research
GeneReviews	RCV000119270	SCV001739285	not provided	Visceral myopathy 1		no assertion provided	literature only	High rate of a poor outcome (mortality and/or multivisceral transplantation) or microcolon