Submissions for variant NM_006005.3(WFS1):c.2347T>C (p.Phe783Leu)

gnomAD frequency: 0.00009  dbSNP: rs71526461

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001722100	SCV000252501	uncertain significance	not provided	2024-08-13	criteria provided, single submitter	clinical testing	Reported in an individual with early-onset diabetes mellitus; patient specific information was not provided (PMID: 37277527); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37277527)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000198824	SCV000966803	uncertain significance	not specified	2018-08-02	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Phe783Leu var iant in WFS1 has not been previously reported in individuals with hearing loss, but has been identified in 0.11% (12/10056) of Ashkenazi Jewish chromosomes and 11/18810 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org/). This variant has been reported in ClinVar (Varia tion ID: 211079). Phenylalanine (Phe) at position 783 is not conserved in mammal s or evolutionarily distant species and 16 species, including 2 mammals, carry a Leucine (Leu) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools suggest that the p.Phe783L eu variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance o f the p.Phe783Leu variant is uncertain, these data suggest that it is more likel y to be benign. ACMG/AMP Criteria applied: BP4.
Illumina Laboratory Services, Illumina	RCV001152301	SCV001313513	uncertain significance	Autosomal dominant nonsyndromic hearing loss 6	2018-01-15	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001152302	SCV001313514	uncertain significance	WFS1-Related Spectrum Disorders	2018-01-15	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001722100	SCV002466375	likely benign	not provided	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517277	SCV003732335	uncertain significance	Inborn genetic diseases	2024-03-05	criteria provided, single submitter	clinical testing	Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003147401	SCV003804313	likely benign	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 rs71526461 in Wolfram's syndrome yet.
CeGaT Center for Human Genetics Tuebingen	RCV001722100	SCV005041965	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	WFS1: BP4, BS2
Fulgent Genetics, Fulgent Genetics	RCV005031736	SCV005667563	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-04-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530177	SCV004115366	uncertain significance	WFS1-related disorder	2024-02-02	no assertion criteria provided	clinical testing	The WFS1 c.2347T>C variant is predicted to result in the amino acid substitution p.Phe783Leu. This variant has been reported in an individual with diabetes (Li et al. 2023. PubMed ID: 37277527). This variant is reported in 0.11% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.