Submissions for variant NM_000352.6(ABCC8):c.1616A>G (p.Tyr539Cys)

dbSNP: rs193922397

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002266905	SCV000051898	likely pathogenic	Maturity onset diabetes mellitus in young	2023-05-04	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.1616A>G (p.Tyr539Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 8e-06 in 623158 control chromosomes (gnomAD and Billings_2022). c.1616A>G has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young (MODY), including one individual with MODY who had an extensive family history of diabetes inherited in an autosomal dominant pattern, however family members were unavailable for genetic testing (e.g. Ates_2021, Ustay_2022, Gokcay Canpolat_2022 (no PMID), Schmidt_2023). These data indicate that the variant is likely to be associated with disease. 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: 34462253, 36208030, 35029855, 37007940). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001823102	SCV002073100	uncertain significance	Diabetes mellitus, transient neonatal, 2		criteria provided, single submitter	clinical testing	The missense variant p.Y539C in ABCC8 (NM_000352.6) has been reported previously as a Likely pathogenic variant in ClinVar database but no details are provided for independent assesment. The p.Y539C variant is observed in 1/1,13,558 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between tyrosine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. For these reasons, this variant has been classified as Uncertain Significance
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002266905	SCV002522379	uncertain significance	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	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 ( rs193922397) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002266906	SCV002522380	uncertain significance	Transitory neonatal diabetes mellitus		criteria provided, single submitter	research	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 ( rs193922397) in neonatal diabetes yet.
Revvity Omics, Revvity	RCV003137542	SCV003824367	uncertain significance	not provided	2023-01-30	criteria provided, single submitter	clinical testing