Submissions for variant NM_000414.4(HSD17B4):c.790A>G (p.Met264Val)

gnomAD frequency: 0.00011  dbSNP: rs149283499

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001152102	SCV001313309	uncertain significance	Bifunctional peroxisomal enzyme deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001152103	SCV001313310	uncertain significance	Perrault syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
New York Genome Center	RCV001152102	SCV001815706	uncertain significance	Bifunctional peroxisomal enzyme deficiency	2020-11-04	criteria provided, single submitter	clinical testing	The homozygous c.790A>G (p.Met264Val) variant identified in the HSD17B4 gene substitutes a moderately conserved Methionine for Valine at amino acid 264/737 (exon 11/24). This variant is found with low frequency in gnomAD (17 heterozygotes, 0 homozygotes; allele frequency: 1.11e-4) suggesting that it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.945) and Benign (REVEL; score:0.261) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:904272), and to our current knowledge has not been reported in affected individuals in the literature. The Met264 residue is within the N-terminal (3R)-hydroxyacyl-CoA dehydrogenase domain of HSD17B4 (UniProtKB:P51659). Given the lack of compelling evidence, the homozygous c.790A>G (p.Met264Val) variant identified in the HSD17B4 gene is reported as a Variant of Uncertain Significance.
Invitae	RCV002557282	SCV003252211	uncertain significance	Bifunctional peroxisomal enzyme deficiency; Perrault syndrome	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 264 of the HSD17B4 protein (p.Met264Val). This variant is present in population databases (rs149283499, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HSD17B4-related conditions. ClinVar contains an entry for this variant (Variation ID: 904272). 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 not expected to disrupt HSD17B4 protein function. 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.