ClinVar Miner

Submissions for variant NM_001291303.3(FAT4):c.9279A>C (p.Gln3093His)

gnomAD frequency: 0.00001  dbSNP: rs769424345
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001004886 SCV001164375 uncertain significance Van Maldergem syndrome 2 2018-12-03 criteria provided, single submitter research The heterozygous p.Gln3091His variant in FAT4 was identified by our study in the compound heterozygous state, with another VUS, in one individual with Van Maldergem syndrome. The p.Gln3091His variant in FAT4 has not been previously reported in individuals with Van Maldergem syndrome and has been identified in 0.007244% (8/110442) of European (non-Finnish) chromosomes and 0.002980% (1/33552) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs769424345). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Gln3091His variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4 (Richards 2015).
GeneDx RCV001759684 SCV001985738 uncertain significance not provided 2020-11-18 criteria provided, single submitter clinical testing Identified with a second missense variant in the FAT4 gene in a male with unilateral renal agenesis, ureterovesical junction obstruction, midface hypoplasia, cryptorchidism, developmental delay, neonatal hypotonia, scoliosis, and camptodactyly of one toe (van der Ven et al., 2017); the variants were reported to segregate in affected siblings although details regarding the number of siblings and their clinical histories were not provided (van der Ven et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28878612, 30143558)
Labcorp Genetics (formerly Invitae), Labcorp RCV001759684 SCV002218979 uncertain significance not provided 2022-08-31 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 3091 of the FAT4 protein (p.Gln3091His). This variant is present in population databases (rs769424345, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of FAT4-related conditions (PMID: 28878612). This variant is also known as c.9279A>C (p.Gln3093His). ClinVar contains an entry for this variant (Variation ID: 813916). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FAT4 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002252296 SCV002523989 uncertain significance See cases 2021-08-31 criteria provided, single submitter clinical testing ACMG classification criteria: PM2, BP4
Fulgent Genetics, Fulgent Genetics RCV005036274 SCV005657502 uncertain significance Van Maldergem syndrome 2; Hennekam lymphangiectasia-lymphedema syndrome 2 2023-12-26 criteria provided, single submitter clinical testing
Yale Center for Mendelian Genomics, Yale University RCV001849467 SCV002106495 likely pathogenic Congenital anomaly of kidney and urinary tract 2018-08-24 no assertion criteria provided literature only

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