Submissions for variant NM_000036.3(AMPD1):c.860A>T (p.Lys287Ile)

gnomAD frequency: 0.02732  dbSNP: rs34526199

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763229	SCV002384066	benign	Muscle AMP deaminase deficiency	2024-02-01	criteria provided, single submitter	clinical testing
Mendelics	RCV002247475	SCV002516860	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002464104	SCV002759362	uncertain significance	Hypercholesterolemia, autosomal dominant, type B; Muscle AMP deaminase deficiency	2022-12-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000763229	SCV003826260	uncertain significance	Muscle AMP deaminase deficiency	2020-02-26	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002247475	SCV004848159	likely benign	not specified	2024-01-01	criteria provided, single submitter	clinical testing	The p.Lys287Ile variant in AMPD1 is classified as likely benign because it has been identified in 13.0% (118/910) of Amish and 8.4% (894/10552) of European chromosomes including 91 homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). ACMG/AMP Criteria applied: BS1.
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.
GenomeConnect, ClinGen	RCV000763229	SCV002075092	not provided	Muscle AMP deaminase deficiency		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 05-17-2017 by Lab or GTR ID 303161. 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.
PreventionGenetics, part of Exact Sciences	RCV003974954	SCV004792752	benign	AMPD1-related disorder	2021-01-28	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).