Submissions for variant NM_000197.2(HSD17B3):c.139A>G (p.Met47Val)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003037330	SCV003441356	uncertain significance	not provided	2022-09-27	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 47 of the HSD17B3 protein (p.Met47Val). This variant is present in population databases (rs191153391, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of androgen synthesis disorder (PMID: 27899157). 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 HSD17B3 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526221	SCV005040503	pathogenic	Testosterone 17-beta-dehydrogenase deficiency	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: HSD17B3 c.139A>G (p.Met47Val) results in a conservative amino acid change in 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 6.4e-05 in 251460 control chromosomes (gnomAD). c.139A>G has been reported in the literature in multiple individuals affected with Testosterone 17-beta-dehydrogenase deficiency (Eggers_2016, Globa_2022, Zidoune_2022, Fujisawa_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and found that it results in ~43% of normal activity (Fujisawa_2023). The following publications have been ascertained in the context of this evaluation (PMID: 27899157, 36110220, 37741351, 33468338, 35432193). ClinVar contains an entry for this variant (Variation ID: 2136797). Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004540509	SCV005040814	pathogenic	Juvenile myoclonic epilepsy	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: EFHC1 c.139A>G (p.Ile47Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.139A>G in individuals affected with Juvenile myoclonic epilepsy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV004526221	SCV005679725	likely pathogenic	Testosterone 17-beta-dehydrogenase deficiency	2024-05-07	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004526221	SCV005849301	likely pathogenic	Testosterone 17-beta-dehydrogenase deficiency	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.139A>G (p.Met47Val) variant in HSD17B3 gene has been reported previously in homozygous/ compound heterozygous states in individuals affected with HSD17B3-related disorders (Eggers et al., 2016; Ea et al., 2021; Globa et al., 2022). This variant was also present in family members of affected individuals (Eggers et al., 2016; Globa et al., 2022; Gonçalves et al., 2022). The p.Met47Val variant is present with allele frequency of 0.006% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Disease causing) predict conflicting evidence on protein structure and function for this variant. The reference amino acid at this position on HSD17B3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 47 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.