ClinVar Miner

Submissions for variant NM_000411.8(HLCS):c.1522C>T (p.Arg508Trp) (rs119103229)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001986 SCV000791240 pathogenic Holocarboxylase synthetase deficiency 2017-05-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000001986 SCV000893549 pathogenic Holocarboxylase synthetase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000001986 SCV000919519 pathogenic Holocarboxylase synthetase deficiency 2018-10-25 criteria provided, single submitter clinical testing Variant summary: HLCS c.1522C>T (p.Arg508Trp) results in a non-conservative amino acid change located in the Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL), catalytic domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant is located at the third exonic nucleotide from a splice junction, suggesting it may impact normal splicing. 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 2.4e-05 in 246292 control chromosomes (gnomAD). The variant, c.1522C>T, has been reported in the literature in multiple homozygous individuals affected with Holocarboxylase Synthetase Deficiency (Malvagia_2005, Tang_2003, Hui_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000001986 SCV000022144 pathogenic Holocarboxylase synthetase deficiency 2001-11-01 no assertion criteria provided literature only

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