Submissions for variant NM_001614.5(ACTG1):c.721G>A (p.Glu241Lys)

dbSNP: rs267606631

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211710	SCV000205640	likely pathogenic	Rare genetic deafness	2016-09-11	criteria provided, single submitter	clinical testing	The p.Glu241Lys variant in ACTG1 has been reported in 3 individuals with hearing loss, segregated in 5 relatives with hearing loss from 2 families (Morin 2009, Miyagawa 2015, LMM unpublished data), and was absent from large population studi es. Functional studies performed in yeast suggested that the variant may impact the hair cell's cytoskeletal structure (Morin 2009). Computational prediction to ols and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clin ical significance, this variant is likely pathogenic for autosomal dominant hear ing loss.
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000019987	SCV000929847	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 20		criteria provided, single submitter	research
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375049	SCV001571715	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Strong, PM2_Moderate, PP3_Supporting
GeneDx	RCV000059728	SCV001786159	likely pathogenic	not provided	2021-05-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as yeast expressing E241K demonstrated impaired growth. E241K also influenced cell morphology and actin cytoskeletal patterns, leading to larger cell size and abnormal randomly distributed thick actin cables and patches as well as an aberrant multi-vacuolar pattern (Morin et al., 2009); 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: 27627659, 19477959, 25792668, 32341388)
Labcorp Genetics (formerly Invitae), Labcorp	RCV005222696	SCV005863198	pathogenic	Autosomal dominant nonsyndromic hearing loss 20; Baraitser-winter syndrome 2	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 241 of the ACTG1 protein (p.Glu241Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant deafness (PMID: 19477959, 25792668). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18322). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTG1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACTG1 function (PMID: 19477959). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000019987	SCV000040285	pathogenic	Autosomal dominant nonsyndromic hearing loss 20	2009-08-15	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000059728	SCV000091298	not provided	not provided		no assertion provided	not provided