ClinVar Miner

Submissions for variant NM_004463.3(FGD1):c.1328G>A (p.Arg443His)

dbSNP: rs137853266
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624593 SCV000741758 likely pathogenic Inborn genetic diseases 2016-08-31 criteria provided, single submitter clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues RCV002060688 SCV002320724 likely pathogenic Aarskog syndrome 2022-03-02 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV003311863 SCV004010942 likely pathogenic not provided 2023-10-01 criteria provided, single submitter clinical testing FGD1: PM2, PM5:Supporting, PP2, PP3, PP4, PS4:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689811 SCV005184722 uncertain significance not specified 2024-05-14 criteria provided, single submitter clinical testing Variant summary: FGD1 c.1328G>A (p.Arg443His) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1328G>A has been reported in the literature in an individual affected with Aarskog Syndrome (Orrico_2004). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 45% reduction in phosphorylation of the downstream target MLK3 and Runx2-responsive OG2-luc activity (Zou_2011). The following publications have been ascertained in the context of this evaluation (PMID: 14560308, 21965325). ClinVar contains an entry for this variant (Variation ID: 521263). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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