Submissions for variant NM_006005.3(WFS1):c.631G>A (p.Asp211Asn)

gnomAD frequency: 0.00004  dbSNP: rs138682654

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196477	SCV000252514	likely pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 22781099, 14676474, 23981289, 26025012, 12707373, 31313226)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196477	SCV002146685	pathogenic	not provided	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 211 of the WFS1 protein (p.Asp211Asn). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs138682654, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 12707373, 22781099, 23981289). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215378). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004020438	SCV004979923	likely pathogenic	Inborn genetic diseases	2022-05-31	criteria provided, single submitter	clinical testing	The c.631G>A (p.D211N) alteration is located in exon 5 (coding exon 4) of the WFS1 gene. This alteration results from a G to A substitution at nucleotide position 631, causing the aspartic acid (D) at amino acid position 211 to be replaced by an asparagine (N). However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing.Based on the available evidence, the WFS1 c.631G>A (p.D211N) alteration is classified as pathogenic for autosomal recessive WFS1-related Wolfram syndrome; however, it is unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome and its clinical significance for autosomal dominant isolated WFS1-related low frequency sensorineural hearing loss is unclear. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (5/278152) total alleles studied. The highest observed frequency was <0.01% (5/126622) of European (non-Finnish) alleles. This alteration was detected in the homozygous state, and in conjunction with other WFS1 alterations, in multiple individuals with autosomal recessive WFS1-related Wolfram syndrome (Marshall, 2013; van ven Ouweland, 2003; Haghighi, 2013; Sobhani, 2019). Based on the available evidence, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005031739	SCV005664690	pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-06-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737310	SCV005346217	likely pathogenic	WFS1-related disorder	2024-09-11	no assertion criteria provided	clinical testing	The WFS1 c.631G>A variant is predicted to result in the amino acid substitution p.Asp211Asn. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Wolfram syndrome (van den Ouweland et al. 2003. PubMed ID: 12707373; Haghighi et al. 2012. PubMed ID: 22781099; Marshall et al. 2013. PubMed ID: 23981289) and also in the heterozygous state in an individual with Wolfram-like syndrome (Table S1, Schlottmann et al. 2023. PubMed ID: 37217489). This variant is reported in 0.0039% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant occurs in the last nucleotide of exon 5 and is predicted to weaken the canonical splice donor site based on available splicing prediction programs (SpliceAI, Jaganathan K, et al. 2019. PubMed ID: 30661751). However, the use of computer prediction programs is not equivalent to functional evidence. This variant is interpreted as likely pathogenic.