Submissions for variant NM_001101.5(ACTB):c.587G>A (p.Arg196His)

dbSNP: rs281875334

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000022439	SCV000246315	pathogenic	Baraitser-Winter syndrome 1	2014-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000059721	SCV000566140	pathogenic	not provided	2021-11-05	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27868373, 22366783, 27625340, 25052316, 27096712, 10928857, 32234145)
CeGaT Center for Human Genetics Tuebingen	RCV000059721	SCV001747497	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
3billion	RCV000022439	SCV002012005	pathogenic	Baraitser-Winter syndrome 1	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novoo in similarly affected indivisual (PMID: 26583190, 2236678, PS2, PS4).The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg196Cys) has been reported as pathogenic/likely pathogenic with strong evidence (PMID:26583190, 22366783, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.817, 3Cnet: 0.884, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV000022439	SCV003439525	pathogenic	Baraitser-Winter syndrome 1	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 196 of the ACTB protein (p.Arg196His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Baraitser-Winter syndrome (PMID: 22366783). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29599). 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 ACTB protein function with a negative predictive value of 80%. This variant disrupts the p.Arg196 amino acid residue in ACTB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22366783, 23756437, 25052316). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000022439	SCV000043728	pathogenic	Baraitser-Winter syndrome 1	2012-02-26	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000059721	SCV000091291	not provided	not provided		no assertion provided	not provided