Submissions for variant NM_000036.3(AMPD1):c.930G>T (p.Met310Ile)

gnomAD frequency: 0.00384  dbSNP: rs61752478

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000514310	SCV000109798	uncertain significance	not provided	2018-07-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000514310	SCV000512022	uncertain significance	not provided	2021-11-01	criteria provided, single submitter	clinical testing	Identified in a patient with familial hypercholesterolemia (Johansen et al., 2014), although the association of this variant with this lipid disorder is unclear; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503134, 26764160, 15173240, 29431110, 32054689, 31130284)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514310	SCV000609529	uncertain significance	not provided	2017-04-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000077969	SCV000755842	likely benign	Muscle AMP deaminase deficiency	2024-01-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514310	SCV000780294	uncertain significance	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000077969	SCV000782670	uncertain significance	Muscle AMP deaminase deficiency	2017-05-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000077969	SCV003826221	uncertain significance	Muscle AMP deaminase deficiency	2019-12-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226192	SCV003922529	uncertain significance	not specified	2023-03-19	criteria provided, single submitter	clinical testing	Variant summary: AMPD1 c.930G>T (p.Met310Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 251424 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency does not allowing conclusions about variant significance, although the presence of homozygotes points to a benign outcome for a condition with full penetrance expected at an early age. Although c.930G>T has been reported in the literature, these report(s) do not provide unequivocal conclusions about association of the variant with Muscle AMP Deaminase Deficiency (example, PMID: 24503134, 31847883). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6; LB, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genomics Laboratory, Stanford Medicine	RCV000077969	SCV004100859	uncertain significance	Muscle AMP deaminase deficiency	2021-01-06	no assertion criteria provided	clinical testing	The p.Met343Ile variant in the AMPD1 gene has been previously reported in at least 3 unrelated individuals, including 1 individual who was heterozygous for this variant with progressive muscle weakness, high creatine, and utilized a wheelchair (Monies et al., 2019), 1 individual with myopathy without information to determine zygosity (Toyama et al., 2004), and at least 1 individual without information regarding clinical features or information to determine zygosity (Reuter et al., 2018). The highest allele frequency of this variant in a non-founder population was identified in the Latino/Admixed American population at 170/35,438 chromosomes (0.48%) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Functional studies of the p.Met343Ile variant are supportive of a deleterious effect to the protein; however, it is unclear if this would be sufficient to be disease-causing (Toyama et al., 2004). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Met343Ile variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP3]