ClinVar Miner

Submissions for variant NM_000036.2(AMPD1):c.1261C>T (p.Arg421Trp) (rs35859650)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522883 SCV000617307 likely pathogenic not provided 2019-01-10 criteria provided, single submitter clinical testing The R421W variant in the AMPD1 gene has been reported previously, using alternate nomenclature of R388W, in trans with the R458H (described as R425H) variant in a 46-year-old Japanese patient with myopathy who had onset of muscle weakness at age 40 (Morisaki et al., 2000). The R421W variant is observed in 74/10,404 alleles (0.7%) from individuals of African background in the ExAC dataset (Lek et al., 2016). The R421W 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. In addition, the R421W substitution occurs at a position that is conserved across species. Expression studies of this variant form of AMPD1 in prokaryotic cells demonstrated undetectable enzyme activity despite normal quantities of AMPD1 peptides as compared with controls (Morisaki et al., 2000). We interpret R421W as a likely pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000522883 SCV000854827 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing
Invitae RCV000019934 SCV001118254 likely benign Muscle AMP deaminase deficiency 2019-12-31 criteria provided, single submitter clinical testing
OMIM RCV000019934 SCV000040232 pathogenic Muscle AMP deaminase deficiency 2000-12-01 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000522883 SCV001553346 uncertain significance not provided no assertion criteria provided clinical testing The AMPD1 p.Arg417Trp variant was identified in dbSNP (ID: rs35859650) and ClinVar (classified as likely pathogenic by GeneDx and as a VUS by EGL Genetic Diagnostics) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 204 of 282854 chromosomes (2 homozygous) at a frequency of 0.000721 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 178 of 24962 chromosomes (freq: 0.007131), Other in 5 of 7226 chromosomes (freq: 0.000692), Latino in 9 of 35440 chromosomes (freq: 0.000254), East Asian in 5 of 19952 chromosomes (freq: 0.000251), European (Finnish) in 3 of 25096 chromosomes (freq: 0.00012) and European (non-Finnish) in 4 of 129192 chromosomes (freq: 0.000031), while the variant was not observed in the Ashkenazi Jewish or South Asian populations. The R417W variant was found in the compound heterozygous state in a Japanese patient with myopathy; expression of the R417W vector compared to wildtype showed no AMPD protein activity from the R417W vector (Morisaki_2000_PMID:11102975). The p.Arg417 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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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