ClinVar Miner

Submissions for variant NM_017612.5(ZCCHC8):c.1487C>T (p.Thr496Ile)

gnomAD frequency: 0.00005  dbSNP: rs369211892
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Johns Hopkins Genomics, Johns Hopkins University RCV001200884 SCV001371789 uncertain significance Pulmonary fibrosis and/or bone marrow failure, telomere-related, 5 2020-01-02 criteria provided, single submitter clinical testing ZCCHC8 c.1487C>T has not been reported in ClinVar nor the literature, to our knowledge. This variant (rs369211892) is rare (<0.1%) in a large population dataset (gnomAD: 5/197308 total alleles; 0.0025%; no homozygotes). Of three bioinformatics tools queried, one predicts that the substitution would be probably damaging, while two predict that it would be tolerated. The threonine residue at this position is highly evolutionarily conserved across most species assessed. We consider the clinical significance of c.1487C>T to be uncertain at this time.
Ambry Genetics RCV004033491 SCV003552692 uncertain significance not specified 2021-10-06 criteria provided, single submitter clinical testing The c.1487C>T (p.T496I) alteration is located in exon 14 (coding exon 14) of the ZCCHC8 gene. This alteration results from a C to T substitution at nucleotide position 1487, causing the threonine (T) at amino acid position 496 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV003718387 SCV004519691 uncertain significance not provided 2022-10-28 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 932915). This variant has not been reported in the literature in individuals affected with ZCCHC8-related conditions. This variant is present in population databases (rs369211892, gnomAD 0.009%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 496 of the ZCCHC8 protein (p.Thr496Ile).

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