Submissions for variant NM_001101.5(ACTB):c.478A>G (p.Thr160Ala)

gnomAD frequency: 0.00001  dbSNP: rs1784814961

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001843426	SCV002589290	likely pathogenic	Baraitser-Winter syndrome 1	2023-02-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 160 of the ACTB protein (p.Thr160Ala). 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: 35401677). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1251980). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001843426	SCV003807145	likely pathogenic	Baraitser-Winter syndrome 1	2022-09-16	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated, PM5 moderated, PP2 supporting, PP3 supporting
Research Laboratory of Ophthalmology and Vision Sciences, West China Hospital, Sichuan University	RCV001843426	SCV001837649	pathogenic	Baraitser-Winter syndrome 1	2021-04-29	no assertion criteria provided	clinical testing	The c.478A>G (p.T160A) variant in ACTB was a de novo heterozygous variant identified in a Chinese family with autosomal dominant Baraitser-Winter syndrome. The variant was reported in dbSNP (rs1784814961) with a frequency of 0.0000 (ALFA) or 0.00007 (gnomAD) in the American population and 0.0000 in Asia. The amino acid site is highly conserved in various animals, and the variant was suggested to be damaging in silico prediction programs. In addition, in vitro cellular functional study suggested the variant affected cytoskeletal organization. Thus, we consider this variant as pathogenic.