ClinVar Miner

Submissions for variant NM_017612.5(ZCCHC8):c.1370A>T (p.Gln457Leu)

gnomAD frequency: 0.00001  dbSNP: rs564778717
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001968480 SCV002239955 uncertain significance not provided 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 457 of the ZCCHC8 protein (p.Gln457Leu). This variant is present in population databases (rs564778717, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ZCCHC8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1462451). 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 ZCCHC8 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.
Johns Hopkins Genomics, Johns Hopkins University RCV003492714 SCV004239015 uncertain significance Pulmonary fibrosis and/or bone marrow failure, telomere-related, 5 2024-01-11 criteria provided, single submitter clinical testing This ZCCHC8 missense variant (rs564778717) is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 7/1465412 total alleles; 0.0005%; no homozygotes). It has been reported in ClinVar (Variation ID 1462451), but has not been reported in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be tolerated, and the glutamine residue at this position is evolutionarily conserved across a few of the species assessed, while most have a different amino acid including several with leucine. We consider the clinical significance of c.1370A>T in ZCCHC8 to be uncertain at this time.

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