ClinVar Miner

Submissions for variant NM_000036.2(AMPD1):c.959A>T (p.Lys320Ile) (rs34526199)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000676655 SCV000109808 uncertain significance not provided 2018-08-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763229 SCV000893862 likely pathogenic Muscle AMP deaminase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000763229 SCV001370453 likely pathogenic Muscle AMP deaminase deficiency 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PP3,PP4.
Mayo Clinic Laboratories, Mayo Clinic RCV000676655 SCV000802449 likely pathogenic not provided 2016-02-23 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000676655 SCV001549476 uncertain significance not provided no assertion criteria provided clinical testing  The AMPD1 p.Lys320Ile variant was identified in the literature as a heterozygous variant in a patient with muscular dystrophy, however this patient also harbored biallelic loss of function variants in the LAMA2 gene that were attributed as the cause of disease (Russo_2014_PMID:25332755). The variant was also identified in dbSNP (ID: rs34526199) and ClinVar (conflicting interpretations of pathogenicity with two likely pathogenic submissions by Fulgent Genetics and Mayo Clinic Genetic Testing Laboratories and one VUS submission by EGL Genetics Diagnostics; associated condition is Muscle AMP deaminase deficiency). The variant was identified in control databases in 8126 of 282682 chromosomes (174 homozygous) at a frequency of 0.028746 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:  European (Finnish) in 2089 of 25116 chromosomes (freq: 0.08317), European (non-Finnish) in 4407 of 129122 chromosomes (freq: 0.03413), Other in 234 of 7220 chromosomes (freq: 0.03241), Ashkenazi Jewish in 252 of 10368 chromosomes (freq: 0.02431), Latino in 553 of 35440 chromosomes (freq: 0.0156), South Asian in 473 of 30614 chromosomes (freq: 0.01545) and African in 118 of 24852 chromosomes (freq: 0.004748), while the variant was not observed in the East Asian population. 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. The p.Lys320 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the K 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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