ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.410G>A (p.Arg137His) (rs146015592)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000021904 SCV000677980 pathogenic Biotinidase deficiency 2014-01-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078072 SCV000230012 pathogenic not provided 2016-10-26 criteria provided, single submitter clinical testing
GeneDx RCV000078072 SCV000329674 pathogenic not provided 2016-05-25 criteria provided, single submitter clinical testing The R157H variant has been described in a large Turkish cohort as the most frequent pathogenic variant associated with biotinidase deficiency, accounting for 32.2% of mutated alleles (Karaca et al., 2015). Most patients in the Turkish cohort who were homozygous for R157H had profound biotinidase deficiency; however, ten R157H homozygous individuals were reported to have partial biotinidase deficiency (Karaca et al., 2015). R157H has also been reported many times in individuals with biotinidase deficiency who harbor a second pathogenic variant in the BTD gene (Pomponio et al., 1997; Karaca et al., 2015; Thodi et al, 2013). Furthermore, a pathogenic variant at the same residue (R157C) and in nearby residues (T152P/R, C160Y, A162V) have also been reported in the Human Gene Mutation Database in association with biotinidase deficiency (Stenson et al., 2014). In summary, we interpret R157H to be a pathogenic variant.
Invitae RCV000021904 SCV000754949 pathogenic Biotinidase deficiency 2017-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 157 of the BTD protein (p.Arg157His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs146015592, ExAC 0.02%). This variant has been reported as homozygous or in combination with another BTD variant in individuals affected with biotinidase deficiency (PMID: 10801053, 11313766, 16435182, 22698809, 27329734) including two individuals in whom the variant has been observed on the opposite chromosome (in trans) from other pathogenic variants (PMID: 20224900, 9396567). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 38290). This variant has been observed in individuals with biotinidase activity < 10% of mean normal serum activity, findings that are highly specific for biotinidase deficicency (PMID: 9396567, 22698809, 11313766, 20224900). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078072 SCV000888018 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000021904 SCV000042601 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only

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