Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002272457 | SCV002557418 | uncertain significance | Fuhrmann syndrome | 2020-05-21 | criteria provided, single submitter | clinical testing | A heterozygous missense variant was identified, NM_004625.3(WNT7A):c.470G>A in exon 3 of 4 of the WNT7A gene. This substitution is predicted to create a minor amino acid change from an arginine to a histidine at position 157 of the protein; NP_004616.2(WNT7A):p.(Arg157His). The arginine at this position has high conservation (100 vertebrates, UCSC), and is located within the WNT superfamily (NCBI). In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a global population frequency of 0.018% (50 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.022%. Two alternative residue changes at the same location has been reported in the gnomAD database at a frequency of 0.0011% and 0.0004% respectively. This variant has not previously been reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VUS. |
| Labcorp Genetics |
RCV001357220 | SCV001632825 | likely benign | not provided | 2024-09-27 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001357220 | SCV001552616 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The WNT7A p.Arg157His variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs199592697) and in control databases in 50 of 282720 chromosomes at a frequency of 0.0001769 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 7 of 7222 chromosomes (freq: 0.000969), South Asian in 7 of 30616 chromosomes (freq: 0.000229), European (non-Finnish) in 29 of 129074 chromosomes (freq: 0.000225), Latino in 5 of 35440 chromosomes (freq: 0.000141) and European (Finnish) in 2 of 25098 chromosomes (freq: 0.00008), but was not observed in the African, Ashkenazi Jewish, or East Asian populations. The p.Arg157 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |