ClinVar Miner

Submissions for variant NM_000036.2(AMPD1):c.133C>T (p.Gln45Ter) (rs17602729)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487355 SCV000568077 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing The Q45X variant in the AMPD1 gene has been reported previously in the compound heterozygous state with another AMPD1 gene variant as well as in the homozygous state in multiple, unrelated individuals with features of adenosine monophosphate deaminase deficiency (Morisaki et al., 1992; Gross et al., 2002; Castro-Gago et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, the Q45X variant is observed in 16,531/126,536 (13.1%) alleles from individuals of non-Finnish European background, including multiple unrelated homozygous individuals, in large population cohorts (Lek et al., 2016). Therefore, we interpret Q45X as a variant of uncertain significance.
Invitae RCV000019933 SCV000755841 uncertain significance Muscle AMP deaminase deficiency 2020-10-07 criteria provided, single submitter clinical testing 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). This variant is present in population databases (rs17602729, ExAC 13%), including over 1000 homozygous individuals, and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with adenosine monophosphate deaminase deficiency (PMID: 1631143, 8335021, 21343608, 15378456). It has also been observed to segregate with disease in related individuals. This variant is also known as c.34C>T (p.Gln12*) in the literature. ClinVar contains an entry for this variant (Variation ID: 18271). Muscle biopsies from affected individuals homozygous for this variant have shown a significant reduction in the enzyme activity of the protein encoded by AMPD1 (PMID: 1631143). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000487355 SCV000854814 other not provided 2018-02-07 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000019933 SCV001366492 uncertain significance Muscle AMP deaminase deficiency 2019-03-21 criteria provided, single submitter clinical testing 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000487355 SCV001446914 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
OMIM RCV000019933 SCV000040231 pathogenic Muscle AMP deaminase deficiency 2011-06-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000019933 SCV000607345 not provided Muscle AMP deaminase deficiency no assertion provided phenotyping only 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000487355 SCV000802453 pathogenic not provided 2016-02-19 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000487355 SCV001551404 uncertain significance not provided no assertion criteria provided clinical testing 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.

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