Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003670030 | SCV004386975 | uncertain significance | not provided | 2024-03-25 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1030 of the NOTCH3 protein (p.Gly1030Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NOTCH3-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH3 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004701765 | SCV005203489 | uncertain significance | not specified | 2024-07-17 | criteria provided, single submitter | clinical testing | Variant summary: NOTCH3 c.3088G>A (p.Gly1030Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position (gnomAD v2). In gnomAD v4, the variant was found in 4 individuals (4/1578600) at an allele frequency of 0.000003. c.3088G>A has been reported in the literature in one individual affected with arcoidosis-associated pulmonary hypertension, without additional evidence for causality (Groen_2022). These report(s) do not provide unequivocal conclusions about association of the variant with NOTCH3-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36292254). ClinVar contains an entry for this variant (Variation ID: 2790697). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Genomic Medicine Center of Excellence, |
RCV004763732 | SCV005373977 | uncertain significance | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2024-09-22 | criteria provided, single submitter | clinical testing |