ClinVar Genomic variation as it relates to human health

Observed de novo as a candidate gene in a patient with jejunal atresia and hyperglycemia (Fakhro et al., 2019); 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 (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31625567, 33710394, 34970864)

This variant appears to occur de novo in multiple individuals with clinical features associated with this gene.

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are suggested mechanisms of disease in this gene. Missense variants are postulated to exert a gain-of-function effect resulting in Baraitser-Winter syndrome 1 (MIM#243310), while loss-of-function variants cause a similar but distinct phenotype (PMIDs: 30733661, 29220674). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (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) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been shown to be de novo in multiple patients (ClinVar, PMID: 31625567). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (VCGS #20W000060, 20W000061 / by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The p.Ser348Leu variant in the ACTB gene has been previously reported de novo in 1 individual with intellectual disability (Clinvar accession: SCV001438279.1) and de novo in 3 individuals with dysmorphic features and developmental delay (Clinvar accession: SCV000329688.5 & GeneDx, personal communication, June 18, 2021). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The ACTB gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that the p.Ser348Leu variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ser348Leu variant as pathogenic for Baraitser-Winter Cerebrofrontofacial Syndrome in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2_VeryStrong; PM2; PP2; PP3]