ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.309C>A (p.Asn103Lys)

gnomAD frequency: 0.00001  dbSNP: rs34227486
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589853 SCV000601270 uncertain significance not provided 2023-07-11 criteria provided, single submitter clinical testing The HBB c.309C>A (p.Asn103Lys) variant (also known as Hb Richmond or CD 102 AAC>AAA or AAG) has been reported in the published literature in heterozygotes with a normal clinical presentation in the published literature (PMID: 4981790 (1969), and 6859036 (1983)). Functional studies suggest this variant may not be damaging to normal function but are inconclusive (PMID: 4981790 (1969), 5283757 (1971), and 239952 (1975)). The frequency of this variant in the general population, 0.0000066 (1/152160 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003387731 SCV000697105 uncertain significance not specified 2023-09-22 criteria provided, single submitter clinical testing Variant summary: HBB c.309C>A (p.Asn103Lys; a.k.a. Hb Richmond) results in a non-conservative amino acid change located in the Globin of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251380 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.309C>A, has been identified in compound heterozygosity with HbS and HbC variants without in vivo sickling and hemolysis. Mild microcytic anemia and polycythemia caused by elevated oxygen affinity, often silent, was also reported. Oxygen affinity studies showed normal readings in the whole blood but slightly higher affinity for oxygen of purified Hb Richmond (Efremov_1969). The variant of interest may be a benign structural variant, however since no reports of homozygosity or compound heterozygosity with B-thal-0 were published at the time of scoring, the clinical significant of Hb Richmond cannot be assessed with confidence. The following publications have been ascertained in the context of this evaluation (PMID: 27207683, 4981790, 26635043, 6859036, 19429541, 19750260, 29365076, 239952, 24200101). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001272124 SCV001453777 uncertain significance beta Thalassemia 2020-09-16 no assertion criteria provided clinical testing

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