ClinVar Miner

Submissions for variant NM_002907.4(RECQL):c.406G>A (p.Val136Ile)

gnomAD frequency: 0.00055  dbSNP: rs138278747
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV003492145 SCV000838650 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001225951 SCV001398245 uncertain significance not provided 2023-12-12 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 136 of the RECQL protein (p.Val136Ile). This variant is present in population databases (rs138278747, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RECQL-related conditions. ClinVar contains an entry for this variant (Variation ID: 584820). 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 RECQL 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.
GeneDx RCV001225951 SCV001827769 likely benign not provided 2021-01-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV004026775 SCV002631379 likely benign not specified 2020-08-26 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.
PreventionGenetics, part of Exact Sciences RCV003953249 SCV004767892 uncertain significance RECQL-related disorder 2023-11-19 no assertion criteria provided clinical testing The RECQL c.406G>A variant is predicted to result in the amino acid substitution p.Val136Ile. This variant was reported in an individual with breast cancer (Table S3, Guindalini. 2022. PubMed ID: 35264596). This variant is reported in 0.18% of alleles in individuals of African descent in gnomAD, and has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/584820/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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