ClinVar Miner

Submissions for variant NM_015634.4(KIFBP):c.599C>A (p.Ser200Ter)

gnomAD frequency: 0.00006  dbSNP: rs730882150
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000325234 SCV000336822 pathogenic not provided 2015-10-28 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001795283 SCV002813831 pathogenic Goldberg-Shprintzen syndrome 2021-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000325234 SCV003923599 pathogenic not provided 2022-11-02 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease (Drvillon et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32939943, 28277559, 23427148)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001795283 SCV004046387 pathogenic Goldberg-Shprintzen syndrome criteria provided, single submitter clinical testing This nonsense variant found in exon 3 of 7 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a homozygous change in two siblings with Goldberg-Shprintzen syndrome (GOSHS) (PMID: 23427148). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (9/282480) and thus is presumed to be rare. Based on the available evidence, the c.599C>A (p.Ser200Ter) variant is classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001795283 SCV004800970 pathogenic Goldberg-Shprintzen syndrome 2024-03-13 criteria provided, single submitter curation The heterozygous p.Ser200Ter variant in KIFBP was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar ID: 300283), in two siblings with congenital fibrosis of the extraocular muscles, hearing impairment, developmental delays, cognitive impairment, scoliosis, Hirschsprung disease, and dysmorphic facial features, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Familial genome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 300283). We believe this is a possible phenotype expansion for Goldberg-Shprintzen megacolon syndrome. The p.Ser200Ter variant in KIFBP has been previously reported in two siblings with Goldberg-Shprintzen megacolon syndrome and segregated with disease in this family (PMID: 23427148), but has been identified in 0.007% (9/128934) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs730882150). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These two affected siblings were homozygotes, which increases the likelihood that the p.Ser200Ter variant is pathogenic (PMID: 23427148). This variant has also been reported in ClinVar (Variation ID: 183145) and has been interpreted as pathogenic by Fulgent Genetics, Eurofins NTD LLC, and OMIM. RT-PCR analysis performed on affected tissue showed significantly reduced mRNA and protein expression versus wild-type (PMID: 23427148). This nonsense variant leads to a premature termination codon at position 200, which is predicted to lead to a truncated or absent protein. Loss of function of the KIFBP gene is an established disease mechanism in Goldberg-Shprintzen megacolon syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Goldberg-Shprintzen megacolon syndrome. ACMG/AMP Criteria applied: PVS1, PS3_Moderate, PM2_Supporting, PM3_Supporting (Richards 2015).
OMIM RCV001795283 SCV000211956 pathogenic Goldberg-Shprintzen syndrome 2013-06-15 no assertion criteria provided literature only

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