Submissions for variant NM_000036.3(AMPD1):c.468G>T (p.Gln156His)

gnomAD frequency: 0.00096  dbSNP: rs139582106

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000443504	SCV000230835	likely pathogenic	not provided	2015-04-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000443504	SCV000512021	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	Reported previously (as Q156H due to alternate nomenclature) in multiple individuals with MADA deficiency and myopathy who were compound heterozygous for the Q189H variant and the most common AMPD1 variant, Q45X (Gross et al., 2002; Neroldova et al., 2016; Rannou et al., 2017); Published functional studies demonstrate altered enzyme activity (Gross et al., 2002); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27296017, 12117480, 29095874, 34426522, 31980526, 32483371, 34269512)
Fulgent Genetics, Fulgent Genetics	RCV000763230	SCV000893863	likely pathogenic	Muscle AMP deaminase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763230	SCV000932594	uncertain significance	Muscle AMP deaminase deficiency	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 189 of the AMPD1 protein (p.Gln189His). This variant is present in population databases (rs139582106, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with myoadenylate deaminase deficiency (PMID: 12117480, 19353846, 29095874). This variant is also known as G468T (Q156H). ClinVar contains an entry for this variant (Variation ID: 197620). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects AMPD1 function (PMID: 12117480). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000763230	SCV001366486	likely pathogenic	Muscle AMP deaminase deficiency	2020-03-24	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000443504	SCV001447000	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000443504	SCV001502536	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	AMPD1: PM3:Very Strong, PM2, PS3:Supporting
Revvity Omics, Revvity	RCV000763230	SCV002021364	likely pathogenic	Muscle AMP deaminase deficiency	2023-03-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000443504	SCV001550920	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The AMPD1 p.Q189H variant was identified in the literature as a compound heterozygous variant in 10 individuals with myoadenylate deaminase deficiency (Gross_2002_PMID_12117480). The variant was identified in dbSNP (ID: rs139582106) and ClinVar (classified as likely pathogenic by EGL Genetic Diagnostics, Fulgent Genetics and GeneDx; classified as uncertain significance by Invitae). The variant was identified in control databases in 147 of 282856 chromosomes at a frequency of 0.0005197 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 115 of 129180 chromosomes (freq: 0.00089), Latino in 25 of 35440 chromosomes (freq: 0.000705), Other in 3 of 7226 chromosomes (freq: 0.000415), African in 2 of 24958 chromosomes (freq: 0.00008) and European (Finnish) in 2 of 25120 chromosomes (freq: 0.00008), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Q189 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. Functional studies have demonstrated altered enzymatic activity from the p.Q189H variant compared to wildtype (Gross_2002_PMID_12117480). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.