Submissions for variant NM_000352.6(ABCC8):c.4544C>T (p.Thr1515Met)

dbSNP: rs769989185

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002004428	SCV002293263	likely pathogenic	not provided	2022-01-18	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is also known as p.Thr1516Met. This missense change has been observed in individual(s) with ABCC8-related early onset diabetes and/or familial hyperinsulinism (PMID: 21378087, 27908292, 33013711). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs769989185, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1515 of the ABCC8 protein (p.Thr1515Met).
MGZ Medical Genetics Center	RCV002290835	SCV002580676	likely pathogenic	Type 2 diabetes mellitus	2022-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699641	SCV005204853	pathogenic	Maturity onset diabetes mellitus in young	2024-06-10	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.4544C>T (p.Thr1515Met) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant disrupts the penultimate nucleotide of exon 37, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site. One predict the variant strengthens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251076 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4544C>T has been reported in the literature in at least one heterozygous individual with congenital hyperinsulinism where the variant was matrnally inherited (e.g., Banerjee_2011) and in several heterozygous individuals affected with Maturity Onset Diabetes Of The Young, where the variant was found to segregate with disease in at least one family (e.g., Lin_2020, Sampathkumar_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21378087, 33013711, 34741762). ClinVar contains an entry for this variant (Variation ID: 1506182). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV002004428	SCV005325033	likely pathogenic	not provided	2024-02-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34014594, 21378087, 33013711, 34741762)