ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.404T>C (p.Val135Ala) (rs33966761)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000855596 SCV000697130 uncertain significance not specified 2019-02-25 criteria provided, single submitter clinical testing Variant summary: HBB c.404T>C (p.Val135Ala), also known as Hb Mataro and Hb Yaounde, results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The sidechain of residue 135 is oriented to the inside of the molecule, and looking toward other hydrophobic residues, therefore replacement of valine by alanine (both having aliphatic side chains of similar size) does not seem to grossly alter the geometry of this region (Arends 1977, Faustino 2004). 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.9e-05 in 277100 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (2.9e-05 vs 1.10e-02), allowing no conclusion about variant significance. The variant, p.Val135Ala, has been reported in the literature in multiple asymptomatic individuals. Faustino_2004 reported a family that carried the variant in trans with HbC (p.Glu7Lys), and concluded that the variant does not cause clinical or hematological manifestations. Yapo_2001 also referred to the variant as neutral, with no hematological consequence, after reporting it in an individual who was compound heterozygous for the variant and Hb Kenitra (p.Gly70Arg). Vinciguerra_2015 reported two family members as compound heterozygotes for this variant and the anti 3.7 alpha-globin gene triplication with no symptoms. These co-occurrences with other pathogenic (or potentially pathogenic) hemoglobin variants in asymptomatic individuals provide a supporting evidence for a benign role. To our knowledge, no experimental evidence evaluating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Taken together, this variant is classified as VUS-possibly benign, until more clinical and functional data becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588829 SCV000889371 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing
OMIM RCV000016855 SCV000037125 other HEMOGLOBIN YAOUNDE 2017-12-12 no assertion criteria provided literature only

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