Submissions for variant NM_000036.3(AMPD1):c.1162C>T (p.Arg388Trp)

gnomAD frequency: 0.00208  dbSNP: rs35859650

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522883	SCV000617307	likely pathogenic	not provided	2024-03-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; specifically, 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 (PMID: 11102975); This variant is associated with the following publications: (PMID: 34426522, Mohamed[article]2023, 10996775, 36846110, 11102975)
Eurofins Ntd Llc (ga)	RCV000522883	SCV000854827	uncertain significance	not provided	2017-09-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000019934	SCV001118254	likely benign	Muscle AMP deaminase deficiency	2024-01-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000019934	SCV002021363	likely pathogenic	Muscle AMP deaminase deficiency	2019-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298446	SCV002599020	uncertain significance	not specified	2022-09-27	criteria provided, single submitter	clinical testing	Variant summary: AMPD1 c.1261C>T (p.Arg421Trp, also known as c.1162C>T, p.Arg388Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 251462 control chromosomes in the gnomAD database, including 1 homozygote. c.1261C>T has been reported as a biallelic genotype in the literature in at least one individual affected with Muscle AMP Deaminase Deficiency (Abe_2000, Morisaki_2000). These data do not allow any conclusion about variant significance. When expressed as a rat/human chimeric protein in a prokaryotic expression assay, the variant was found to potentially induce loss of function. However, it is not clear if this effect can be replicated in human cells with human mutant protein (Morisaki_2000). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely pathogenic, and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
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.