ClinVar Miner

Submissions for variant NM_004260.4(RECQL4):c.1903C>T (p.His635Tyr)

gnomAD frequency: 0.00001  dbSNP: rs758743745
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000634262 SCV000755565 uncertain significance Baller-Gerold syndrome 2025-01-28 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 635 of the RECQL4 protein (p.His635Tyr). This variant is present in population databases (rs758743745, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 528965). 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 RECQL4 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.
Ambry Genetics RCV002529823 SCV003693512 uncertain significance Inborn genetic diseases 2020-12-10 criteria provided, single submitter clinical testing The c.1903C>T (p.H635Y) alteration is located in exon 12 (coding exon 12) of the RECQL4 gene. This alteration results from a C to T substitution at nucleotide position 1903, causing the histidine (H) at amino acid position 635 to be replaced by a tyrosine (Y). The p.H635Y alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003444611 SCV004171472 uncertain significance Rothmund-Thomson syndrome type 2 2023-10-16 criteria provided, single submitter clinical testing The RECQL4 c.1903C>T (p.His635Tyr) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools are inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with RECQL4-associated conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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