Submissions for variant NM_000883.4(IMPDH1):c.769A>G (p.Thr257Ala)

gnomAD frequency: 0.00040  dbSNP: rs144659635

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000287544	SCV000466753	uncertain significance	Leber congenital amaurosis 11	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000347099	SCV000466754	likely benign	Retinitis pigmentosa	2018-01-13	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.
GeneDx	RCV000521919	SCV000619747	uncertain significance	not provided	2017-08-10	criteria provided, single submitter	clinical testing	The T257A variant in the IMPDH1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T257A variant is observed in 33/15946 (0.2%) alleles from individuals of South Asian background, in the ExAC dataset (Lek et al., 2016). The T257A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T257A as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000521919	SCV001611939	likely benign	not provided	2023-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003168555	SCV003862488	uncertain significance	Inborn genetic diseases	2023-02-16	criteria provided, single submitter	clinical testing	The c.769A>G (p.T257A) alteration is located in exon 8 (coding exon 8) of the IMPDH1 gene. This alteration results from a A to G substitution at nucleotide position 769, causing the threonine (T) at amino acid position 257 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genetics, Academic Medical Center	RCV000521919	SCV001918679	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000521919	SCV001969172	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544684	SCV004769608	likely benign	IMPDH1-related disorder	2020-04-29	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).