Submissions for variant NM_002500.5(NEUROD1):c.964G>A (p.Ala322Thr)

gnomAD frequency: 0.00003  dbSNP: rs754458532

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001138780	SCV001298858	likely benign	Maturity-onset diabetes of the young type 6	2018-01-12	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856777	SCV002226017	uncertain significance	not provided	2021-08-23	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NEUROD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 896247). This variant is present in population databases (rs754458532, ExAC 0.1%). This sequence change replaces alanine with threonine at codon 322 of the NEUROD1 protein (p.Ala322Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine.
New York Genome Center	RCV002468178	SCV002764396	uncertain significance	Maturity-onset diabetes of the young type 6; Type 2 diabetes mellitus	2021-10-18	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003890287	SCV004705513	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Ambry Genetics	RCV004032326	SCV004984143	likely benign	Inborn genetic diseases	2023-12-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV004754694	SCV005347833	uncertain significance	NEUROD1-related disorder	2024-03-12	no assertion criteria provided	clinical testing	The NEUROD1 c.964G>A variant is predicted to result in the amino acid substitution p.Ala322Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.14% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.