ClinVar Miner

Submissions for variant NM_001374353.1(GLI2):c.4241C>T (p.Pro1414Leu)

gnomAD frequency: 0.00005  dbSNP: rs749402521
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000591031 SCV000704455 uncertain significance not provided 2016-12-29 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000591031 SCV004149121 likely benign not provided 2022-11-01 criteria provided, single submitter clinical testing GLI2: BP4, BS2
Ambry Genetics RCV004984996 SCV005596383 likely benign Inborn genetic diseases 2024-11-14 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV005223025 SCV005865997 uncertain significance Holoprosencephaly 9; Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome 2024-06-28 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1431 of the GLI2 protein (p.Pro1431Leu). This variant is present in population databases (rs749402521, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GLI2-related conditions. ClinVar contains an entry for this variant (Variation ID: 499120). 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 GLI2 protein function with a negative 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.

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