Submissions for variant NM_006005.3(WFS1):c.1243_1245del (p.Val415del)

dbSNP: rs863224265

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199829	SCV000252550	pathogenic	not provided	2022-10-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect resulting in decreased wolframin expression compared to the wildtype (Rendtorff et al., 2011); In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21067485, 28432734, 16151413, 21446023, 15277431, 18806274, 21538838, 10521293, 21602428, 8808601, 27617222, 19042979, 23429432, 31600780)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000611263	SCV000731608	pathogenic	Rare genetic deafness	2017-04-14	criteria provided, single submitter	clinical testing	The p.Val415del variant in WFS1 has been reported in >10 individuals with Wolfra m syndrome (Hardy 1999, Smith 2004, Hansen 2005, Gasparin 2009, Chaussenot 2011, Rohayem 2011, Rendtorff 2011, de Heredia ML 2013, Bodoor 2016) and segregated i n 7 affected relatives (Hardy 1999, Hansen 2005, Gasparin 2009, Rendtorff 2011, Bodoor 2016). All of these individuals were homozygous or compound heterozygous. This variant has also been reported in ClinVar (Variation ID: 215406). This var iant was identified in 9/33582 Latino chromosomes by the Genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750767821); however, its frequency is low enough to be consistent with a recessive carrier frequency. In addition, in vitro studies suggest that the p.Val415del variant may impact expr ession of WFS1 (Rendtorff 2011). In summary, this variant meets criteria to be c lassified as pathogenic for autosomal recessive Wolfram syndrome based upon repo rted familial cases, low frequency in controls, and functional evidence.
DASA	RCV001849340	SCV002107143	pathogenic	WFS1-Related Spectrum Disorders	2022-03-05	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21538838) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 215406; PMID: 27617222; PMID: 23429432; PMID: 19042979) - PS4. The variant is present at low allele frequencies population databases (rs863224265 – gnomAD 0.0008545%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Val415del) was detected in trans with a pathogenic variant (PMID: 27617222; PMID: 19042979) - PM3. Protein length variants as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - PM4. The variant co-segregated with disease in multiple affected family members (PMID: 27617222) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199829	SCV002217148	pathogenic	not provided	2024-08-08	criteria provided, single submitter	clinical testing	This variant, c.1243_1245del, results in the deletion of 1 amino acid(s) of the WFS1 protein (p.Val415del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750767821, gnomAD 0.03%). This variant has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 10521293, 21067485, 27617222, 31600780). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215406). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002478696	SCV002799720	pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV001843422	SCV000044807	pathogenic	Wolfram syndrome 1	2011-06-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004541271	SCV004798201	pathogenic	WFS1-related disorder	2024-02-23	no assertion criteria provided	clinical testing	The WFS1 c.1243_1245delGTC variant is predicted to result in an in-frame deletion (p.Val415del). This sequence variant has been documented to be causative for Wolfram syndrome (Hardy et al. 1999. PubMed ID: 10521293; Smith et al. 2004. PubMed ID: 15277431; Hansen et al. 2005. PubMed ID: 16151413; Gasparin et al. 2009. PubMed ID: 19042979; Marshall et al. 2013. PubMed ID: 23981289). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.