Browsing by Subject "ClinGen"

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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 Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants.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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    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.