ClinVar Miner

Submissions for variant NM_001101.5(ACTB):c.1043C>T (p.Ser348Leu)

dbSNP: rs886041309
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000370520 SCV000329688 pathogenic not provided 2023-08-25 criteria provided, single submitter clinical testing 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)
CeGaT Center for Human Genetics Tuebingen RCV000370520 SCV001155017 likely pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing
Center for Statistical Genetics, Columbia University RCV001261369 SCV001438279 pathogenic Intellectual disability 2020-10-16 criteria provided, single submitter research
Clinical Genetics and Genomics, Karolinska University Hospital RCV000370520 SCV001450129 likely pathogenic not provided 2016-09-09 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470832 SCV002769447 pathogenic Baraitser-Winter syndrome 1 2020-10-19 criteria provided, single submitter clinical testing 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
Baylor Genetics RCV002470832 SCV003836010 pathogenic Baraitser-Winter syndrome 1 2022-11-07 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000370520 SCV002817297 uncertain significance not provided 2021-05-04 flagged submission clinical testing This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Molecular Genetics laboratory, Necker Hospital RCV000370520 SCV004031375 likely pathogenic not provided 2021-03-11 no assertion criteria provided clinical testing
Clinical Genomics Program, Stanford Medicine RCV002470832 SCV004228498 pathogenic Baraitser-Winter syndrome 1 2021-06-30 no assertion criteria provided clinical testing 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]

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