Submissions for variant NM_005609.4(PYGM):c.1859T>C (p.Ile620Thr)

gnomAD frequency: 0.00034  dbSNP: rs142008108

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001103025	SCV001259735	uncertain significance	Glycogen storage disease, type V	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV001355325	SCV002541151	uncertain significance	not provided	2021-07-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001103025	SCV002790802	uncertain significance	Glycogen storage disease, type V	2022-03-01	criteria provided, single submitter	clinical testing
Invitae	RCV001103025	SCV003517458	uncertain significance	Glycogen storage disease, type V	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 620 of the PYGM protein (p.Ile620Thr). This variant is present in population databases (rs142008108, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with PYGM-related conditions. ClinVar contains an entry for this variant (Variation ID: 877372). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PYGM protein function. 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.
Revvity Omics, Revvity	RCV001103025	SCV003818079	uncertain significance	Glycogen storage disease, type V	2022-08-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001103025	SCV001467650	uncertain significance	Glycogen storage disease, type V	2020-04-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355325	SCV001550186	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PYGM p.Ile620Thr variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs142008108) and in control databases in 61 of 282786 chromosomes at a frequency of 0.000216 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 20 of 35438 chromosomes (freq: 0.000564), European (non-Finnish) in 37 of 129116 chromosomes (freq: 0.000287), African in 3 of 24958 chromosomes (freq: 0.00012) and European (Finnish) in 1 of 25122 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, East Asian, Other or South Asian populations. The p.Ile620 residue is conserved across mammals and other organisms, and four out of five 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. 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. 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.