ClinVar Genomic variation as it relates to human health

The SRD5A3 c.951_955delGTTTT (p.Phe318SerfsTer2) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL 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 for this variant, it 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 and cDNA change, and amino acid change. No publications were found based on this search. This variant is located in the last 50 bp of the last exon and may escape nonsense-mediated decay. Due to the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 318 of the SRD5A3 protein (p.Phe318Ser). This variant is present in population databases (rs565935886, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SRD5A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 632442). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

Observed in individuals with blindness and Peters anomaly in published literature, however, detailed clinical and segregation information was not provided (Dineiro et al., 2020; Chesneau et al., 2022); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32483926, 35170016)

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type Iq congenital disorder of glycosylation (MIM#612379) and Kahrizi syndrome (MIM#612713). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to serine at the final amino acid residue; the effect on 3'UTR is unknown. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (149 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated 3-oxo-5-alpha-steroid 4-dehydrogenase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as VUS multiple times in ClinVar and LOVD. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The c.951_955delGTTTT (p.F318Sfs*2) alteration, located in exon 5 (coding exon 5) of the SRD5A3 gene, consists of a deletion of 5 nucleotides from position 951 to 955, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.