ClinVar Miner

Submissions for variant NM_175875.5(SIX5):c.191C>T (p.Pro64Leu)

gnomAD frequency: 0.00001  dbSNP: rs1192927373
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001769737 SCV002004642 likely benign not provided 2020-01-30 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV004671436 SCV005166678 uncertain significance not specified 2024-04-08 criteria provided, single submitter clinical testing The c.191C>T (p.P64L) alteration is located in exon 1 (coding exon 1) of the SIX5 gene. This alteration results from a C to T substitution at nucleotide position 191, causing the proline (P) at amino acid position 64 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005023248 SCV005647951 uncertain significance Branchiootorenal syndrome 2 2024-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001769737 SCV005745046 uncertain significance not provided 2025-01-19 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 64 of the SIX5 protein (p.Pro64Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SIX5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1317730). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SIX5 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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