ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2603G>A (p.Arg868His) (rs56393026)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199675 SCV000252547 likely pathogenic not provided 2013-08-27 criteria provided, single submitter clinical testing p.Arg868His (CGC>CAC): c.2603 G>A in exon 8 of the WFS1 gene (NM_006005.3) The likely pathogenic R868H missense change identified in the WFS1 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. R868H is a conservative amino acid substitution as Arginine and Histidine are both positively charged, polar residues. However, the variant alters a highly conserved position in the WFS1 gene and multiple in silico algorithms predict that R868H is damaging to the structure/function of the protein. Furthermore, missense mutations at nearby positions (H860D, E864K, D866N and V871M) have been previously reported in association with Wolfram syndrome, autosomal dominant optic atrophy with hearing impairment, Wolframin variant, and type 1 diabetes and sensorineural hearing loss respectively. Therefore, R868H is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded.Wofram syndrome is an autosomal recessive neurodegenerative disorder characterized by onset of diabetes mellitus and optic atrophy before age 15 years and is usually associated with sensorineural hearing loss, progressive neurological abnormalities, and other endocrine abnormalities (Tranebjaerg et al., 2009). Autosomal dominant inheritance of WFS1 mutations have been reported in association with Wolfram syndrome-like disease in two families with low-frequency sensorineural hearing loss, diabetes mellitus, psychiatric illness and in one family, optic atrophy (Tranebjaerg et al., 2009). The variant is found in MITONUC-MITOP panel(s).
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000502304 SCV000598135 uncertain significance Autistic behavior 2017-03-22 criteria provided, single submitter clinical testing This heterozygous variant in the WFS1 gene (autosomal recessive transmission), inherited from the mother, was present in a male child who also harbours a second variant in the same gene inherited by the father (compound heterozygosity).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000199675 SCV000709484 uncertain significance not provided 2017-06-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001156283 SCV001317771 uncertain significance Autosomal dominant nonsyndromic deafness 6 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001156284 SCV001317772 uncertain significance WFS1-Related Spectrum Disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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