ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.62T>A (p.Val21Asp)

gnomAD frequency: 0.00004  dbSNP: rs200670692
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588969 SCV000696592 pathogenic Familial hyperinsulinism 2017-02-23 criteria provided, single submitter clinical testing Variant summary: The ABCC8 c.62T>A (p.Val21Asp) variant causes a missense change involving the alteration of a conserved nucleotide. Although the variant is located outside of any known functional domain of the ATP-regulated potassium channels, 5/5 in silico tools predict a deleterious outcome for this variant. This variant was found in 12/88122 control chromosomes at a frequency of 0.0001362, which does not exceed the estimated maximal expected allele frequency of a pathogenic ABCC8 variant (0.0033541). Furthermore, this variant was identified homozygously or in compound heterozygosity in multiple diazoxide-unresponsive comprehensively genotyped neonatal patients with biochemically and histologically confirmed diagnosed diffuse CHI which is inherited in an autosomal recessive manner. Although no in-vitro functional studies supporting a loss of function of the ATP regulated potassium channels have been reported, the available patient characteristics provide in-vivo evidence demonstrating a damaging effect of this variant on channel function. Taken together, the ascertained evidence has been weighted to classify this variant as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001386147 SCV001586279 pathogenic not provided 2024-01-07 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 21 of the ABCC8 protein (p.Val21Asp). This variant is present in population databases (rs200670692, gnomAD 0.01%). This missense change has been observed in individuals with recessive congenital hyperinsulinism (PMID: 19475716, 20685672, 23345197). ClinVar contains an entry for this variant (Variation ID: 495835). 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 ABCC8 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 27573238). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002491164 SCV002775702 likely pathogenic Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 2021-10-15 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000666072 SCV004026592 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2023-08-16 criteria provided, single submitter curation The p.Val21Asp variant in ABCC8 has been reported in at least 6 individuals with hyperinsulinemic hypoglycemia (PMID: 16357843, 19475716, 20685672, 23345197, 23275527), and has been identified 0.011% (14/122860) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200670692). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 495835) and has been interpreted as pathogenic/likely pathogenic by Invitae, Natera Inc., Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Counsyl and Fulgent Genetics. Of the many affected individuals, 4 were compound heterozygotes that carried a reported pathogenic variant in trans, and 1 was a homozygote, which increases the likelihood that the p.Val21Asp variant is pathogenic (Variation ID: 633026; PMID: 16357843, 19475716, 20685672, 23345197, 23275527). In vitro functional studies provide some evidence that the p.Val21Asp variant may slightly impact protein function (PMID: 27573238). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very_strong, PP3, PS3_supporting (Richards 2015).
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV004545790 SCV004046431 pathogenic ABCC8-related disorder criteria provided, single submitter clinical testing This variant has been previously reported as homozygous and compound heterozygous change in patients with congenital hyperinsulinemic hypoglycemia (PMID: 23345197, 19475716). The c.62T>A (p.Val21Asp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (15/271858) and is absent in the homozygous state, thus is presumed to be rare. The c.62T>A (p.Val21Asp) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.62T>A (p.Val21Asp) variant is classified as Pathogenic.
Baylor Genetics RCV003459458 SCV004198945 pathogenic Type 2 diabetes mellitus 2024-02-04 criteria provided, single submitter clinical testing
Counsyl RCV000666072 SCV000790310 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2017-03-11 no assertion criteria provided clinical testing
Natera, Inc. RCV001829617 SCV002081240 pathogenic Hereditary hyperinsulinism 2021-04-30 no assertion criteria provided clinical testing

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