Submissions for variant NM_005609.4(PYGM):c.2312G>A (p.Arg771Gln)

gnomAD frequency: 0.00004  dbSNP: rs150911354

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493384	SCV000582885	pathogenic	not provided	2023-08-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 18846642, 19670320, 35022222, 34534370, 21802952)
Counsyl	RCV000669086	SCV000793790	uncertain significance	Glycogen storage disease, type V	2017-08-30	criteria provided, single submitter	clinical testing
Invitae	RCV000669086	SCV000832062	pathogenic	Glycogen storage disease, type V	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 771 of the PYGM protein (p.Arg771Gln). This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. This variant is present in population databases (rs150911354, gnomAD 0.005%). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 19670320, 21802952, 34534370, 35022222; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 430153). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Columbia University Laboratory of Personalized Genomic Medicine, Columbia University Medical Center	RCV000669086	SCV001977607	likely pathogenic	Glycogen storage disease, type V	2021-10-11	criteria provided, single submitter	clinical testing	The c. 2312G>A(p.Arg771Gln) variant identified in this individual is a missense variant in coding exon 18/20 that substitutes a conserved arginine residue to glutamine at amino acid 771/843. In silico methods predict this variant to be tolerated/damaging (SIFT: 0.165; Provean:-3.38) to protein function. This variant is also predicted to affect splicing as it lies in the last nucleotide of exon 18, which is part of the consensus splice donor site for this exon (Trap Score: 0.989; dbscSNV: 0.9999). This variant is present at an allele frequency of 2/282862, zero homozygotes in gnomAD exomes and genomes, suggesting that it is not a common benign variant in the populations represented in these databases. This variant has been previously reported in affected individuals, once homozygous, once compound heterozygous with the pathogenic p.Arg50Ter PYGM variant (Nadaj-Pakleza, 2009; Vieitez, 2011), and was detected homozygous from proband only clinical WES in an affected individual at CUMC. Based on the currently available evidence, we classify this variant as likely pathogenic.
Baylor Genetics	RCV000669086	SCV004207223	likely pathogenic	Glycogen storage disease, type V	2023-10-10	criteria provided, single submitter	clinical testing