Submissions for variant NM_006005.3(WFS1):c.647C>G (p.Pro216Arg)

gnomAD frequency: 0.00032  dbSNP: rs141233896

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445466	SCV000537006	uncertain significance	Monogenic diabetes	2015-10-13	criteria provided, single submitter	research	ACMG Criteria: PP3, BP4
GeneDx	RCV000766821	SCV000618546	uncertain significance	not provided	2024-10-23	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000518948	SCV000711245	uncertain significance	not specified	2017-02-02	criteria provided, single submitter	clinical testing	The p.Pro216Arg variant in WFS1 has not been previously reported in individuals with hearing loss, Wolfram syndrome, or Wolfram-like disorder. This variant has been identified in 0.07% (5/7552) of African chromosomes and 0.02% (10/497210) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs141233896). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. Computational prediction tools and conservation analysis do not provide str ong support for or against an impact to the protein. In summary, the clinical si gnificance of the p.Pro216Arg variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766821	SCV002447274	likely benign	not provided	2024-12-30	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002509072	SCV002773859	uncertain significance	Wolfram syndrome 1		criteria provided, single submitter	research	Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs141233896 in Wolfram's syndrome yet.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000518948	SCV005423222	uncertain significance	not specified	2024-10-16	criteria provided, single submitter	clinical testing	Variant summary: WFS1 c.647C>G (p.Pro216Arg) results in a non-conservative amino acid change located in the Wolframin, EF-hand domain of 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 6.6e-05 in 244194 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in WFS1 causing Wolfram Syndrome 1, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.647C>G in individuals affected with Wolfram Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 393386). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005033961	SCV005664692	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-03-22	criteria provided, single submitter	clinical testing