ClinVar Miner

Submissions for variant NM_000036.2(AMPD1):c.567G>T (p.Gln189His) (rs139582106)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000443504 SCV000230835 likely pathogenic not provided 2015-04-07 criteria provided, single submitter clinical testing
GeneDx RCV000443504 SCV000512021 likely pathogenic not provided 2018-10-17 criteria provided, single submitter clinical testing The Q189H variant in the AMPD1 gene has been reported previously (as Q156H due to alternate nomenclature) in ten individuals with MADA deficiency and myopathy who were compound heterozygous for the Q189H variant and the most common AMPD1 variant, a C34-T transition in mRNA (Gross et al., 2002). Q189H has also been previously reported in association with hypercholesterolemia, however familial segregation information, in vitro functional studies, or additional clinical information were not included (Neroldová et al., 2016). Enzyme assays showed that the Q189H variant was associated with altered enzyme activity (Gross et al., 2002). Additionally, Q189H is reported as a likely pathogenic variant in ClinVar by a different clinical laboratory (ClinVar SCV000230835.2; Landrum et al., 2015). The Q189H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. The Q189H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Fulgent Genetics,Fulgent Genetics RCV000763230 SCV000893863 likely pathogenic Muscle AMP deaminase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000763230 SCV000932594 uncertain significance Muscle AMP deaminase deficiency 2019-04-16 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 189 of the AMPD1 protein (p.Gln189His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs139582106, ExAC 0.08%). This variant has been observed in several individuals affected with myoadenylate deaminase deficiency (PMID: 12117480, 27296017). This variant is also known as Gln156His in the literature. ClinVar contains an entry for this variant (Variation ID: 197620). This variant has been reported to affect AMPD1 protein function (PMID: 12117480). 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000763230 SCV001366486 likely pathogenic Muscle AMP deaminase deficiency 2020-03-24 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000443504 SCV001447000 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000443504 SCV001502536 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000443504 SCV001550920 likely pathogenic not provided no assertion criteria provided clinical testing The AMPD1 p.Q189H variant was identified in the literature as a compound heterozygous variant in 10 individuals with myoadenylate deaminase deficiency (Gross_2002_PMID_12117480). The variant was identified in dbSNP (ID: rs139582106) and ClinVar (classified as likely pathogenic by EGL Genetic Diagnostics, Fulgent Genetics and GeneDx; classified as uncertain significance by Invitae). The variant was identified in control databases in 147 of 282856 chromosomes at a frequency of 0.0005197 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 115 of 129180 chromosomes (freq: 0.00089), Latino in 25 of 35440 chromosomes (freq: 0.000705), Other in 3 of 7226 chromosomes (freq: 0.000415), African in 2 of 24958 chromosomes (freq: 0.00008) and European (Finnish) in 2 of 25120 chromosomes (freq: 0.00008), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Q189 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. Functional studies have demonstrated altered enzymatic activity from the p.Q189H variant compared to wildtype (Gross_2002_PMID_12117480). 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 pathogenic role for this variant. This variant is classified as likely pathogenic.

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