ClinVar Miner

Submissions for variant NM_001354604.2(MITF):c.997G>A (p.Glu333Lys)

gnomAD frequency: 0.00001  dbSNP: rs147682682
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000659864 SCV000781746 uncertain significance Waardenburg syndrome type 2A 2016-11-01 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV001270110 SCV001448958 uncertain significance not provided 2019-04-04 criteria provided, single submitter clinical testing
GeneDx RCV001270110 SCV002562400 uncertain significance not provided 2023-05-09 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD)
Invitae RCV002530560 SCV003214371 uncertain significance Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8 2023-12-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 226 of the MITF protein (p.Glu226Lys). This variant is present in population databases (rs147682682, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MITF-related conditions. ClinVar contains an entry for this variant (Variation ID: 547533). 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 expected to disrupt MITF protein function with a positive predictive value of 80%. 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.
Ambry Genetics RCV004026048 SCV003542857 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-10 criteria provided, single submitter clinical testing The c.676G>A (p.E226K) alteration is located in exon 7 (coding exon 7) of the MITF gene. This alteration results from a G to A substitution at nucleotide position 676, causing the glutamic acid (E) at amino acid position 226 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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