ClinVar Genomic variation as it relates to human health

This variant is interpreted as a Likely pathogenic for Intellectual developmental disorder with severe speech and ambulation defects, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PS4-Moderate, PM6, PP3.

This variant was identified as de novo (maternity and paternity confirmed).

PS3, PM2, PM6, PP3, PP4, PP5

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28135719, 28867141, 28628100, 31031012, 28191890, 26582918, 32873422, 32312822, 31036916, 34008892, 31785789)

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with a neurodevelopmental disorder with severe speech and ambulation defects (PMID: 31031012). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430804). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 343 of the ACTL6B protein (p.Gly343Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine.

The c.1027G>A (p.G343R) alteration is located in exon 12 (coding exon 12) of the ACTL6B gene. This alteration results from a G to A substitution at nucleotide position 1027, causing the glycine (G) at amino acid position 343 to be replaced by an arginine (R)._x000D_ _x000D_ Based on the available evidence, the ACTL6B c.1027G>A (p.G343R) alteration is classified as pathogenic for ACTL6B-related neurodevelopmental disorder; however, its clinical significance for ACTL6B-related developmental and epileptic encephalopathy is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or germline mosaicism in multiple individuals with clinical features of ACTL6B-related neurodevelopmental disorder (Bell, 2019). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive developmental and epileptic encephalopathy (MIM#618468). Gain of function is postulated for autosomal dominant intellectual developmental disorder with severe speech and ambulation defects (MIM#618470). (I) 0108 - This gene is associated with both recessive and dominant disease. While the genotype-phenotype correlation is currently unestablished, only two variants have been reported for the autosomal dominant condition, p.(Asp77Gly) and p.(Gly343Arg) (PMID: 31031012). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated actin domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by mulitple clinical laboratories in ClinVar and observed as de novo in several individuals with intellectual developmental disorder with severe speech and ambulation defects (MIM#618470; PMID: 31031012). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Variant confirmed as disease-causing by referring clinical team

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP5.