Submissions for variant NM_000036.3(AMPD1):c.1974+1G>A

gnomAD frequency: 0.00004  dbSNP: rs145328844

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001574991	SCV001801898	uncertain significance	not provided	2020-04-08	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV002569077	SCV003300898	uncertain significance	Muscle AMP deaminase deficiency	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14 of the AMPD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in AMPD1 cause disease. This variant is present in population databases (rs145328844, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with AMPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1207113). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Revvity Omics, Revvity	RCV002569077	SCV003826242	uncertain significance	Muscle AMP deaminase deficiency	2021-12-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226480	SCV003922538	uncertain significance	not specified	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: AMPD1 c.1974+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. One in silico tool predicting splice impact predicts the variant to be probably pathogenic (TrAP). The variant allele was found at a frequency of 7.6e-05 in 251408 control chromosomes. To our knowledge, no occurrence of c.1974+1G>A in individuals affected with Muscle AMP Deaminase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Currently, it is not clear if loss-of-function is a mechanism of disease for AMPD1. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003956269	SCV004771123	uncertain significance	AMPD1-related disorder	2023-10-18	no assertion criteria provided	clinical testing	The AMPD1 c.2073+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-115216529-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.