Browsing by Subject "Variant interpretation"

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    Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel
    (Springer Nature, 2019-11) Shen, Jun; Oza, Andrea M.; Del Castillo, Ignacio; Duzkale, Hatice; Matsunaga, Tatsuo; Pandya, Arti; Kang, Hyunseok P.; Mar-Heyming, Rebecca; Guha, Saurav; Moyer, Krista; Lo, Christine; Kenna, Margaret; Alexander, John J.; Zhang, Yan; Hirsch, Yoel; Luo, Minjie; Cao, Ye; Choy, Kwong Wai; Cheng, Yen-Fu; Avraham, Karen B.; Hu, Xinhua; Garrido, Gema; Moreno-Pelayo, Miguel A.; Greinwald, John; Zhang, Kejian; Zeng, Yukun; Brownstein, Zippora; Basel-Salmon, Lina; Davidov, Bella; Frydman, Moshe; Weiden, Tzvi; Nagan, Narasimhan; Willis, Alecia; Hemphill, Sarah E.; Grant, Andrew R.; Siegert, Rebecca K.; DiStefano, Marina T.; Amr, Sami S.; Rehm, Heidi L.; Abou Tayoun, Ahmad N.; Clin Gen Hearing Loss Working Group; Biostatistics, School of Public Health
    Purpose: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants. Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed. Results: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants. Conclusion: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
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    Functional Analysis of G6PD Variants Associated With Low G6PD Activity in the All of Us Research Program
    (medRxiv, 2024-04-14) Powell, Nicholas R.; Geck, Renee C.; Lai, Dongbing; Shugg, Tyler; Skaar, Todd C.; Dunham, Maitreya; Medicine, School of Medicine
    Glucose-6-phosphate dehydrogenase (G6PD) protects red blood cells against oxidative damage through regeneration of NADPH. Individuals with G6PD polymorphisms (variants) that produce an impaired G6PD enzyme are usually asymptomatic, but at risk of hemolytic anemia from oxidative stressors, including certain drugs and foods. Prevention of G6PD deficiency-related hemolytic anemia is achievable through G6PD genetic testing or whole-genome sequencing (WGS) to identify affected individuals who should avoid hemolytic triggers. However, accurately predicting the clinical consequence of G6PD variants is limited by over 800 G6PD variants which remain of uncertain significance. There also remains significant variability in which deficiency-causing variants are included in pharmacogenomic testing arrays across institutions: many panels only include c.202G>A, even though dozens of other variants can also cause G6PD deficiency. Here, we seek to improve G6PD genotype interpretation using data available in the All of Us Research Program and using a yeast functional assay. We confirm that G6PD coding variants are the main contributor to decreased G6PD activity, and that 13% of individuals in the All of Us data with deficiency-causing variants would be missed if only the c.202G>A variant were tested for. We expand clinical interpretation for G6PD variants of uncertain significance; reporting that c.595A>G, known as G6PD Dagua or G6PD Açores, and the newly identified variant c.430C>G, reduce activity sufficiently to lead to G6PD deficiency. We also provide evidence that five missense variants of uncertain significance are unlikely to lead to G6PD deficiency, since they were seen in hemi- or homozygous individuals without a reduction in G6PD activity. We also applied the new WHO guidelines and were able to classify two synonymous variants as WHO class C. We anticipate these results will improve the accuracy, and prompt increased use, of G6PD genetic tests through a more complete clinical interpretation of G6PD variants. As the All of Us data increases from 245,000 to 1 million participants, and additional functional assays are carried out, we expect this research to serve as a template to enable complete characterization of G6PD deficiency genotypes. With an increased number of interpreted variants, genetic testing of G6PD will be more informative for preemptively identifying individuals at risk for drug- or food-induced hemolytic anemia.
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    Specifications of the ACMG/AMP guidelines for ACADVL variant interpretation
    (Elsevier, 2023) Flowers, May; Dickson, Alexa; Miller, Marcus J.; Spector, Elaine; Enns, Gregory Mark; Baudet, Heather; Pasquali, Marzia; Racacho, Lemuel; Sadre-Bazzaz, Kianoush; Wen, Ting; Fogarty, Melissa; Fernandez, Raquel; Weaver, Meredith A.; Feigenbaum, Annette; Graham, Brett H.; Mao, Rong; Medical and Molecular Genetics, School of Medicine
    Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is a relatively common inborn error of metabolism, but due to difficulty in accurately predicting affected status through newborn screening, molecular confirmation of the causative variants by sequencing of the ACADVL gene is necessary. Although the ACMG/AMP guidelines have helped standardize variant classification, ACADVL variant classification remains disparate due to a phenotype that can be nonspecific, the possibility of variants that produce late-onset disease, and relatively high carrier frequency, amongst other challenges. Therefore, an ACADVL-specific variant curation expert panel (VCEP) was created to facilitate the specification of the ACMG/AMP guidelines for VLCADD. We expect these guidelines to help streamline, increase concordance, and expedite the classification of ACADVL variants.