Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000710395 | SCV000840607 | uncertain significance | not provided | 2017-12-07 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002493255 | SCV002781132 | uncertain significance | Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 | 2021-07-07 | criteria provided, single submitter | clinical testing | |
| New York Genome Center | RCV003336161 | SCV004046568 | uncertain significance | Hyperinsulinemic hypoglycemia, familial, 1 | 2022-10-26 | criteria provided, single submitter | clinical testing | The c.647G>A variant in ABCC8 has previously been reported in an individual with hyperphagic obesity with hyperglycemia and hypertension along with a likely pathogenic variant in the MRAP2 gene [PMID:31700171] and it has been deposited in ClinVar [ClinVar ID: 585350] as Variant of Uncertain Significance. The c.647G>A variant is observed in 33 alleles (~0.006% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All ofUs), suggesting it is not a common benign variant in the populations represented in those databases. The c.647G>A variant is located in exon 5 of this 39-exon gene and is predicted to replace an arginine amino acid with histidine at position 216 (p.(Arg216His)). In silico predictions for p.(Arg216His) are inconclusive of the variant’s effect [(CADD v1.6 = 24.8, REVEL = 0.599)]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.647G>A p.(Arg216His) variant identified in ABCC8 is classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004702369 | SCV005202986 | uncertain significance | not specified | 2024-07-22 | criteria provided, single submitter | clinical testing | Variant summary: ABCC8 c.647G>A (p.Arg216His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251482 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (4e-05 vs 0.0034), allowing no conclusion about variant significance. c.647G>A has been reported in the literature in one individual affected with Hyperinsulinism, co-occurring with a missense change in MRAP2 (Baron_NM_2019), and in another individual with pulmonary arterial hypertension (Zhu_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31700171, 31727138). ClinVar contains an entry for this variant (Variation ID: 585350). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Natera, |
RCV001830572 | SCV002081129 | uncertain significance | Hereditary hyperinsulinism | 2019-10-28 | no assertion criteria provided | clinical testing |