Submissions for variant NM_000207.3(INS):c.227G>A (p.Ser76Asn)

gnomAD frequency: 0.00050  dbSNP: rs139264769

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001355710	SCV002567281	uncertain significance	not provided	2022-02-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
New York Genome Center	RCV002468238	SCV002764490	uncertain significance	Type 1 diabetes mellitus 2; Maturity-onset diabetes of the young type 10; Hyperproinsulinemia	2022-01-03	criteria provided, single submitter	clinical testing	The c.227G>A (p.Ser76Asn) variant identified in the INS gene substitutes a Serine for Asparagine at amino acid 76/111 (exon 3/3). This variant is found with low frequency in gnomAD(v3.1.2)(75 heterozygotes, 0 homozygotes, allele frequency:4.928e-4), suggesting it is not a benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.593) and Benign (REVEL; score:0.1739) to the function of the canonical transcript. This variant is reported as Likely Benign in ClinVar (VarID:1049511), and was identified in a single patient with Maturity Onset Diabetes in the Young (MODY) although with unclear clinical significance [PMID:31595705]. Given the lack of compelling evidence for its pathogenicity, the c.227G>A (p.Ser76Asn) variant identified in the INS gene is reported as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001355710	SCV003269658	uncertain significance	not provided	2024-02-07	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 76 of the INS protein (p.Ser76Asn). This variant is present in population databases (rs139264769, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with INS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049511). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003388002	SCV004099629	likely benign	not specified	2023-09-08	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355710	SCV001550667	likely benign	not provided		no assertion criteria provided	clinical testing	The INS p.Ser76Asn variant was identified in 1 of 102 Brazilian individuals with maturity-onset diabetes of the young (MODY) (de Santana_2019_PMID:31595705). The variant was identified in dbSNP (ID: rs139264769) and LOVD 3.0 but was not identified in ClinVar. The variant was identified in control databases in 34 of 243736 chromosomes at a frequency of 0.0001395 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 32 of 21820 chromosomes (freq: 0.001467) and Other in 2 of 6444 chromosomes (freq: 0.00031), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), and South Asian populations. The p.Ser76 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.