Submissions for variant NM_024592.5(SRD5A3):c.951_955del (p.Phe318fs)

dbSNP: rs565935886

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779445	SCV000916065	uncertain significance	SRD5A3-congenital disorder of glycosylation	2018-11-21	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000779445	SCV000932036	uncertain significance	SRD5A3-congenital disorder of glycosylation	2022-09-07	criteria provided, single submitter	clinical testing	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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270115	SCV001448972	uncertain significance	Low-set ears; Hemangioma; Generalized hypotonia	2019-12-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001528813	SCV001822758	uncertain significance	not provided	2023-05-11	criteria provided, single submitter	clinical testing	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)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000779445	SCV002557933	uncertain significance	SRD5A3-congenital disorder of glycosylation	2022-03-31	criteria provided, single submitter	clinical testing	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
Fulgent Genetics, Fulgent Genetics	RCV002507348	SCV002802054	uncertain significance	SRD5A3-congenital disorder of glycosylation; Kahrizi syndrome	2022-04-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002535656	SCV003691117	uncertain significance	Inborn genetic diseases	2022-10-13	criteria provided, single submitter	clinical testing	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528813	SCV001741199	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528813	SCV001929333	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528813	SCV001970116	uncertain significance	not provided		no assertion criteria provided	clinical testing