Submissions for variant NM_000352.6(ABCC8):c.3517G>A (p.Val1173Met)

gnomAD frequency: 0.00002  dbSNP: rs141322087

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234919	SCV000051901	uncertain significance	not specified	2023-05-04	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.3517G>A (p.Val1173Met) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 1.2e-05 in 251412 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3517G>A has been reported in the literature in at-least one MODY diagnosed patient that also had a co-occurrence in GCK c.943C>T (Yalcintepe_2021) as well as individuals not affected with diabetes (Billings_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Neonatal Diabetes Mellitus. 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: 36208030, 33565752). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196917	SCV001367551	uncertain significance	Permanent neonatal diabetes mellitus	2018-10-24	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP5.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249021	SCV001422928	uncertain significance	Monogenic diabetes	2020-01-22	criteria provided, single submitter	curation	The p.Val1173Met variant in ABCC8 has been reported in 1 individual with Monogenic Diabetes in ClinVar (Variation ID: 35609), and has been identified in 0.003098% (4/129110) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141322087). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 35609). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Val1173Met variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4 (Richards 2015).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002243661	SCV002515431	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 ( rs141322087) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002243662	SCV002515432	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 ( rs141322087) in neonatal diabetes yet.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626670	SCV000747372	likely pathogenic	Atrial septal defect; Short stature; Feeding difficulties; Hypoglycemia; Growth delay; Congestive heart failure; Macrotia; Macrocephaly; Small for gestational age; Cardiac shunt; Gastroesophageal reflux; Neonatal respiratory distress	2017-01-01	flagged submission	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001725116	SCV001960132	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001725116	SCV001962822	uncertain significance	not provided		no assertion criteria provided	clinical testing