ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.410G>A (p.Gly137Asp) (rs33949486)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282296 SCV000603900 likely benign none provided 2020-06-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000016385 SCV000697131 likely benign not specified 2019-08-02 criteria provided, single submitter clinical testing Variant summary: HBB c.410G>A (p.Gly137Asp) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251372 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.410G>A has been widely reported in the literature as a clinically innocuous variant in individuals with mildly anemic phenotypes and also in co-occurrence among individuals with HbCS, Hb-H disease, and HbE/beta-thallasemia (Minnich_1965, Ingle_2004, Enoki_1989, Martinez_1984, Pagnier_1978, Sura_2007, Beneitez_2006, Fucharoen_2012, Svasti_2001, Chunpanich_2004, Rahbar_1992, Pillers_1992, Delacour_2016, Srivorakun_2014). In particular, compound heterozygous individuals with Hb-Hope-HbS genotypes did not present with sickle cell disease phenotype (Ingle_2004). These data indicate that the variant is not strongly associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Enoki_1989). The most pronounced variant effect results in reduced oxygen affinity. One clinical diagnostic laboratory and OMIM have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000029996 SCV001138214 benign beta Thalassemia 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004558 SCV001163640 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284489 SCV001470316 uncertain significance not provided 2020-06-08 criteria provided, single submitter clinical testing
OMIM RCV000016385 SCV000036653 benign not specified 2017-12-12 no assertion criteria provided literature only

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