Submissions for variant NM_006005.3(WFS1):c.2648_2651del (p.Phe883fs)

dbSNP: rs797045076

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191146	SCV000245555	pathogenic	Wolfram syndrome 1	2015-05-04	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a missense variant [C755R] in a 38-year-old female with Asperger, ataxia, optic atrophy, progressive vision impairment, spastic bladder, chronic fatigue, irregular menses. Variant is pathogenic in recessive state. Found once in our laboratory heterozygous in a 48-year-old male with type 2 diabetes and family history of sudden death.
GeneDx	RCV000200365	SCV000252562	pathogenic	not provided	2022-12-27	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11260218, 26633545, 10521293, 16151413, 26875006, 30507261, 33841295, 23748048)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200365	SCV001409808	pathogenic	not provided	2024-10-26	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the WFS1 gene (p.Phe883Serfs*68). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acid(s) of the WFS1 protein and extend the protein by 59 additional amino acid residues. This variant is present in population databases (rs772120569, gnomAD 0.02%). This frameshift has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 10521293, 11260218, 16151413, 28432734). This variant is also known as 2646-2649del. ClinVar contains an entry for this variant (Variation ID: 209207). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000200365	SCV001500780	pathogenic	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001536011	SCV001752691	pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2021-06-30	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000191146	SCV002605571	likely pathogenic	Wolfram syndrome 1		criteria provided, single submitter	research	Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs797045076 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000191146	SCV003807645	pathogenic	Wolfram syndrome 1	2022-09-08	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 very strong, PP1 strong
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000191146	SCV005397469	pathogenic	Wolfram syndrome 1	2022-03-24	criteria provided, single submitter	clinical testing	This sequence variant is a 4 nucleotide deletion (delTCTT) in exon 8 of 8 in the WFS1 gene that causes a frameshift at codon 883, elimites the canonical stop codon, and introduces 68 novel amino acids to the end of the WFS1-encoded protein, wolframin. This variant is predicted to alter the structure of the wolframin endoplasmic reticulum lumen domain (PMID: 10521293), which is critical for wolframin's function. This is a previously reported variant (ClinVar) that has been observed to segregate in families and individuals affected by Wolfram syndrome in both the homozygous and compound heterozygous states (PMID: 10521293, 1615141, 15605410, 11260218, 16151413, 28432734, 34006618). This variant is rare in control population datasets (gnomAD database, 26 of 281,428 alleles, 0.009%). Functiol studies provide contradictory evidence on the effect this variant has on mR expression and the endoplasmic reticulum stress response but suggest that this variant destabilizes wolframin, leading to its degradation and the death of the cell (PMID: 33879153, 34006618). Given this evidence, we consider this a pathogenic variant. ACMG Criteria: PM3, PS3, PVS1
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000191146	SCV005398145	pathogenic	Wolfram syndrome 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive Wolfram syndrome (MIM#222300). Dominant-negative is suggested for heterozygous missense variants causing autosomal dominant Wolfram-like syndrome (MIM#614296) (PMID: 32219690). (I) 0108 - This gene is associated with both recessive and dominant disease. Both deafness (MIM#600965) and Wolfram syndrome (MIM#222300) are inherited in an autosomal dominant manner while Wolfram-like syndrome (MIM#614296). A clear-genotype-phenotype correlation is currently unestablished. (I) 0208 - Variant is predicted to result in an elongated protein. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 26 heterozygotes, 0 homozygotes). (SP) 0703 - Other elongation variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. At least two others have been reported in individuals with Wolfram syndrome (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity for the recessive form of the disease in unrelated individuals. It has been reported in at least ten individuals with Wolfram syndrome in both homozygous and compound heterozygous states. It has also been classified as pathogenic by diagnostic laboratories in ClInvar (PMID: 10521293, 11260218, 15605410, 16151413, 28432734). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000191146	SCV000024952	pathogenic	Wolfram syndrome 1	2024-03-06	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000200365	SCV001919781	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000200365	SCV001970440	likely pathogenic	not provided		no assertion criteria provided	clinical testing