ClinVar Miner

Submissions for variant NM_001101.5(ACTB):c.209C>T (p.Pro70Leu)

dbSNP: rs587779769
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268259 SCV001447057 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000133565 SCV002557522 pathogenic Baraitser-Winter syndrome 1 2022-06-24 criteria provided, single submitter clinical testing 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 ACTB -related neurodevelopmental disorder. However, gain of function, dominant negative and loss of function are suggested mechanisms for variants associated with Baraitser-Winter syndrome (MIM#243310; PMID: 29220674). The mechanism of juvenile-onset dystonia (MIM#607371) is unclear. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. High clinical variability has been observed between individuals with Baraitser-Winter syndrome who harbour the same variant (PMID: 26583190, PMID: 30315159). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline 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) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Pro70Ala)) has been reported as de novo in an individual with Baraitser-Winter syndrome (BWS; PMID: 30733661). Another comparable variant (p.(Pro70His)) has been reported as a VUS (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been observed once as de novo, and reported as pathogenic and likely pathogenic in an additional three unrelated individuals with BWS (LOVD, ClinVar, PMID: 26275891, PMID: 25052316). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 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
Department of Genetics, Robert DEBRE University Hospital RCV000133565 SCV000148635 pathogenic Baraitser-Winter syndrome 1 2014-04-15 no assertion criteria provided clinical testing

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