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

gnomAD frequency: 0.00004  dbSNP: rs149399432

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000674861	SCV001236127	pathogenic	Holocarboxylase synthetase deficiency	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 634 of the HLCS protein (p.Asp634Asn). This variant is present in population databases (rs149399432, gnomAD 0.006%). This missense change has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 12633764, 17274881). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558569). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HLCS protein function with a positive predictive value of 80%. 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. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000674861	SCV002060376	uncertain significance	Holocarboxylase synthetase deficiency	2021-10-20	criteria provided, single submitter	clinical testing	NM_000411.6(HLCS):c.1900G>A(D634N) is a missense variant classified as a variant of uncertain significance in the context of holocarboxylase synthetase deficiency. D634N has been observed in cases with relevant disease (PMID: 12633764, 17274881, 16134170). Functional assessments of this variant are not available in the literature. D634N has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000411.6(HLCS):c.1900G>A(D634N) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002232807	SCV002511496	uncertain significance	not specified	2022-04-12	criteria provided, single submitter	clinical testing	Variant summary: HLCS c.1900G>A (p.Asp634Asn) results in a conservative amino acid change located in the Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL), catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251496 control chromosomes. c.1900G>A has been reported in the literature in individuals affected with Holocarboxylase Synthetase Deficiency. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV003328619	SCV004035702	likely pathogenic	not provided	2023-03-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16134170, 25087612, 12633764, 17274881)
Natera, Inc.	RCV000674861	SCV002083720	uncertain significance	Holocarboxylase synthetase deficiency	2021-10-13	no assertion criteria provided	clinical testing