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 RCV000588829 SCV000697130 uncertain significance not provided 2017-01-20 criteria provided, single submitter clinical testing Variant summary: The HBB c.404T>C (p.Val135Ala) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4/121400 control chromosomes at a frequency of 0.0000329, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in multiple individuals. Faustino _2004 reported a family that carries the variant in trans with HbC (p.Glu7Lys), and concluded that the variant does not cause clinical or hematological manifestations and Yapo_2001 also referred to the variant as neutral, with no hematological consequence, in an individual who is compound heterozygous for the variant and Hb Kenitra (p.Gly70Arg). Vinciguerra_2015 reported two family members as compund het for variant and aaa anti 3.7 with no symptoms. Arends_1977 reported that the peptide /betaTpXIV (beta133-144) contains three valine residues, at positions 133, 134 and 137, all of which are internal, non-polar residues. Thus substitution of a nonpolar internally located amino acid, Valine, by similar amino acid, Alanine, is not expected to deteriorate the tertiary structure of the HBB protein. Taken together, this variant is classified as VUS-possibly benign until more clinical and functional data becomes available.
OMIM RCV000016855 SCV000037125 other HEMOGLOBIN YAOUNDE 2017-12-12 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588829 SCV000889371 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing

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