Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001158038 | SCV001319652 | uncertain significance | Familial hypoparathyroidism | 2017-04-28 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
| Fulgent Genetics, |
RCV002491458 | SCV002782532 | uncertain significance | Hyperparathyroidism 4; Hypoparathyroidism, familial isolated, 2 | 2022-02-19 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001357755 | SCV003261929 | uncertain significance | not provided | 2023-10-13 | 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 107 of the GCM2 protein (p.Asp107Asn). This variant is present in population databases (rs61741855, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary hyperparathyroidism (PMID: 31671402). ClinVar contains an entry for this variant (Variation ID: 907881). 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 GCM2 protein function. 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001357755 | SCV001553319 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The GCM2 p.Asp107Asn variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs61741855), Cosmic (FATHMM predicted pathogenic; score=1.00) and LOVD 3.0. The variant was also identified in control databases in 150 of 280948 chromosomes at a frequency of 0.000534 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 32 of 30616 chromosomes (freq: 0.001045), European (non-Finnish) in 100 of 127922 chromosomes (freq: 0.000782), Other in 4 of 7214 chromosomes (freq: 0.000555), Latino in 13 of 35436 chromosomes (freq: 0.000367) and African in 1 of 24948 chromosomes (freq: 0.00004); it was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Asp107 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. |