ClinVar Genomic variation as it relates to human health

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP4,BA1,BS2.

This sequence change creates a premature translational stop signal (p.Gln45*) in the AMPD1 gene. However, alternative splicing may rescue certain truncations, particularly those occurring in exon 2 (PMID: 1922051). It is expected to result in an absent or disrupted protein product. 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 (rs17602729, gnomAD 13%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with adenosine monophosphate deaminase deficiency (PMID: 1631143, 8335021, 15378456, 21343608). It has also been observed to segregate with disease in related individuals. This variant is also known as c.34C>T (p.Gln12*). ClinVar contains an entry for this variant (Variation ID: 18271). 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.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21686757, 29143670, 29095874, 25525159, 8335021, 32596782, 32483371, 33250842, 15239633, 15378456, 14499869, 23300193, 16021918, 18855224, 1631143, 12117480, 21343608, 10918252, 29422864, 29749052, 30429902, 28751290, 30837873, 31867206, 32379996, 24508110, 35309536, 33879512, 35821574, 36112609, 32639377)

Variant summary: AMPD1 c.34C>T (p.Gln12X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Most truncations downstream of this position have been classified as uncertain significance in ClinVar. The variant allele was found at a frequency of 0.086 in 251114 control chromosomes, predominantly at a frequency of 0.13 within the Non-Finnish European subpopulation in the gnomAD database, including 986 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.16 fold of the estimated maximal expected allele frequency for a pathogenic variant in AMPD1 causing Muscle AMP Deaminase Deficiency phenotype (0.11), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.34C>T has been reported in the literature in multiple homozygous and heterozygous individuals affected with Muscle AMP Deaminase Deficiency (Morisaki_1992, Rannou_2017). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in decreasing normal AMPD activity (Morisaki_1992, Kalsi_2003, Rannou_2017). Seven ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=3), uncertain significance (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

AMPD1: BS1, BS2

The AMPD1 p.Gln45* variant has been reported in multiple homozygous individuals with AMPD deficiency but has also been reported in multiple healthy controls, including athletes (Morisaki_1992_PMID:1631143; Gronek_2018_PMID:30429902; Nikolova_2015_PMID:26380113; Gineviciene_2014_PMID:24885427). The variant was identified in dbSNP (ID: rs17602729) and ClinVar (classified as uncertain significance by GeneDx and Invitae, and as pathogenic by Mayo Clinic). The variant was identified in control databases in 24609 of 282334 chromosomes (1470 homozygous) at a frequency of 0.08716 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 16882 of 128928 chromosomes (freq: 0.1309), European (Finnish) in 2903 of 25048 chromosomes (freq: 0.1159), Other in 682 of 7188 chromosomes (freq: 0.09488), Ashkenazi Jewish in 790 of 10360 chromosomes (freq: 0.07625), Latino in 1757 of 35356 chromosomes (freq: 0.04969), South Asian in 1078 of 30602 chromosomes (freq: 0.03523), African in 516 of 24900 chromosomes (freq: 0.02072), and East Asian in 1 of 19952 chromosomes (freq: 0.00005). The c.133C>T variant leads to a premature stop codon at position 45, which is predicted to lead to a truncated or absent protein and loss of function. It is unclear how loss of function variants of the AMPD1 gene contribute to autosomal recessive AMPD deficiency; further, many individuals with AMPD deficiency are asymptomatic. The p.Gln45* variant occurs in the last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, three of four 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. This variant is classified as a variant of uncertain significance.

The p.Gln45* variant in the AMPD1 gene has been previously reported in >20 unrelated individuals, some were asymptomatic and others had features consistent with myoadenylate deaminase deficiency. All individuals were homozygous/compound heterozygous although some had variants in other genes that may be alternate explanations for those individuals’ features (Castro-Gago et al., 2011; Morisaki et al., 1992; Pantoja-Martinez et la., 2004; Rannou et al, 2017; Rubio et al., 2000). The highest allele frequency of the p.Gln45* variant was identified in the European population at 16,882/128,928 chromosomes (13.09%) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant leads to a premature stop codon in exon 2 of 16 coding exons and is therefore predicted to undergo nonsense-mediated decay resulting in a truncated or absent protein. Loss of AMPD1 function is a possible mechanism of disease, and data from functional studies suggests this gene is intolerant to variants that result in loss of function (Castro-Gago et al., 2011; Morisaki et al., 1992). Functional studies of the p.Gln45* variant are supportive of a deleterious effect to the protein; however, it is unclear if this would be sufficient to be disease-causing (Castro-Gago et al., 2011; Morisaki et al., 1992). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gln45* variant is uncertain due to conflicting allele frequency, clinical, and functional evidence. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PVS1_moderate; PS3_moderate]

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).

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.