ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs33966761
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855596 SCV000697130 uncertain significance not specified 2023-10-23 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). The variant allele was found at a frequency of 3.2e-05 in 251372 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any 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, and hematological parameters comparable to individuals carrying only the other variant. These co-occurrences with other pathogenic (or potentially pathogenic) hemoglobin variants in asymptomatic individuals provide supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 891976, 33851260, 15481891, 19429541, 21353607, 26635043, 17932132, 11523095, 31553106, 25113778, 19500561, 11300355, 15065210). Two ClinVar submitters (evaluation after 2014) cites the variant as uncertain significance, while another ClinVar submitter (evaluation after 2014) cites it as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional evidence of clinical and or functional importance becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588829 SCV000889371 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV000588829 SCV001449725 pathogenic not provided 2018-04-12 criteria provided, single submitter clinical testing
OMIM RCV000016855 SCV000037125 other HEMOGLOBIN YAOUNDE 2017-12-12 no assertion criteria provided literature only
Natera, Inc. RCV001835629 SCV002089183 uncertain significance beta Thalassemia 2018-05-11 no assertion criteria provided clinical testing

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