Submissions for variant NM_006005.3(WFS1):c.1148G>A (p.Arg383His)

gnomAD frequency: 0.00008  dbSNP: rs369450642

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001519101	SCV001727909	benign	not provided	2024-07-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002501816	SCV002807068	likely benign	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2021-07-23	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001519101	SCV005298380	benign	not provided		criteria provided, single submitter	not provided
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789643	SCV005399332	likely benign	Wolfram syndrome 1	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_006005.3(WFS1):c.1148G>A in exon 8 of 8 of the WFS1 gene. This substitution is predicted to create a minor amino acid change from arginine to histidine at position 383 of the protein, NP_005996.2(WFS1):p.(Arg383His). The arginine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.09% (24 heterozygotes, 2 homozygotes) in the South Asian subpopulation. Three alternative residue changes at the same location have been reported in the gnomAD database. The variant has been previously reported likely benign (LOVD, VKGL-NL_Leiden). A different variant in the same codon resulting in a change to cysteine has also been reported in Asian patients with type 2 diabetes or autosomal dominant hearing loss, however pathogenicity remains unclear (Kawamoto, T. et al., 2004; Iwasa, Y.I. et al., 2016). Based on information available at the time of curation, this variant has been classified as LIKELY BENIGN. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
GeneDx	RCV001519101	SCV005870293	uncertain significance	not provided	2024-08-19	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35791237)
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001519101	SCV002035735	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001519101	SCV002038294	likely benign	not provided		no assertion criteria provided	clinical testing