ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.2635G>A (p.Asp879Asn)

gnomAD frequency: 0.00006  dbSNP: rs531684936
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000290773 SCV000369311 uncertain significance Diabetes mellitus, transient neonatal, 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000331715 SCV000369312 uncertain significance Permanent neonatal diabetes mellitus 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000386179 SCV000369313 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genetic Services Laboratory, University of Chicago RCV001820892 SCV002065330 uncertain significance not specified 2021-07-23 criteria provided, single submitter clinical testing DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.2635G>A, in exon 22 that results in an amino acid change, p.Asp879Asn. This sequence change has been described in the gnomAD database with a frequency of 0.037% in the African/African-American subpopulation (dbSNP rs531684936). The p.Asp879Asn change affects a moderately conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp879Asn substitution. This sequence change does not appear to have been previously described in individuals with ABCC8-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp879Asn change remains unknown at this time.
Fulgent Genetics, Fulgent Genetics RCV002480109 SCV002789409 uncertain significance Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 2024-04-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002520699 SCV003273202 likely benign not provided 2024-01-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV002520700 SCV003638203 uncertain significance Inborn genetic diseases 2022-07-30 criteria provided, single submitter clinical testing The c.2635G>A (p.D879N) alteration is located in exon 22 (coding exon 22) of the ABCC8 gene. This alteration results from a G to A substitution at nucleotide position 2635, causing the aspartic acid (D) at amino acid position 879 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001820892 SCV005394443 uncertain significance not specified 2024-09-13 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.2635G>A (p.Asp879Asn) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251482 control chromosomes, predominantly at a frequency of 0.00037 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2635G>A has been reported in the literature in one individual affected with permanenent neonatal diabetes mellitus, co-occurring with a de novo pathogenic variant in ABCC8 (L225P) (Masia_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. 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: 17317760). ClinVar contains an entry for this variant (Variation ID: 303771). Based on the evidence outlined above, the variant was classified as uncertain significance.

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