ClinVar Miner

Submissions for variant NM_001352514.2(HLCS):c.2341G>A (p.Asp781Asn) (rs149399432)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674861 SCV000800263 uncertain significance Holocarboxylase synthetase deficiency 2018-05-29 criteria provided, single submitter clinical testing
Invitae RCV000674861 SCV001236127 uncertain significance Holocarboxylase synthetase deficiency 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 634 of the HLCS protein (p.Asp634Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs149399432, ExAC 0.01%). This variant has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 12633764, 17274881). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558569). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Asp634 amino acid residue in HLCS. Other variant(s) that disrupt this residue have been observed in individuals with HLCS-related conditions (PMID: 11735028), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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