rs1554943599
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000352.6(ABCC8):c.524T>A(p.Leu175Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,452,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L175L) has been classified as Likely benign.
Frequency
Consequence
NM_000352.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.524T>A | p.Leu175Gln | missense_variant | 4/39 | ENST00000389817.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.524T>A | p.Leu175Gln | missense_variant | 4/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000431 AC: 1AN: 231976Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 124732
GnomAD4 exome AF: 0.00000413 AC: 6AN: 1452124Hom.: 0 Cov.: 32 AF XY: 0.00000416 AC XY: 3AN XY: 720974
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Aug 16, 2023 | The p.Leu175Gln variant in ABCC8 has been previously reported in 1 individual with hyperinsulinemic hypoglycemia (PMID: 23275527), and has been seen in 0.001% (1/104792) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs1554943599). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 557284) and has been interpreted as a variant of uncertain significance by Counsyl and Clinical Genomics (Uppaluri K&H Personalized Medicine Clinic). 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, the clinical significance of the p.Leu175Gln variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting (Richards 2015). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 14, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | Variant summary: ABCC8 c.524T>A (p.Leu175Gln) 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 variant allele was found at a frequency of 4.3e-06 in 231976 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.524T>A has been reported in the literature in at-least one individual affected with Congenital Hyperinsulinism (example: Snider_2013). This report does not provide unequivocal conclusions about association of the variant with Congenital 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: 23275527). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Maturity onset diabetes mellitus in young Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs1554943599) in MODY yet. - |
Transitory neonatal diabetes mellitus Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs1554943599) in neonatal diabetes yet. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at