Submissions for variant NM_005609.4(PYGM):c.2125TTC[1] (p.Phe710del)

dbSNP: rs527236147

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000128553	SCV000220502	likely pathogenic	Glycogen storage disease, type V	2014-07-10	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000128553	SCV000915541	pathogenic	Glycogen storage disease, type V	2017-07-10	criteria provided, single submitter	clinical testing	The PYGM c.2128_2130delTTC (p.Phe710del) variant result in an inframe deletion. Across a selection of the available literature, the p.Phe710del variant has been identified in a total of 13 individuals with glycogen storage disease type V including 11 in a homozygous state and two in a compound heterozygous state (Tsujino et al. 1994; Tsujino et al. 1994; Sugie et al. 1995; Park et al. 2014; Inal-Gültekin et al. 2017). Six of the homozygous patients were pairs of siblings. The second variant in the compound heterozygous patients was either a frameshift resulting in premature termination or an unidentified variant that resulted in weak gene expression. The p.Phe710del variant segregated with disease in one family that consisted of two affected homozygous siblings and two unaffected heterozygous carrier parents (Tsujino et al. 1994a). The p.Phe710del variant was absent from 163 controls (Tsujino et al. 1994a; Sugie et al. 1995; Inal-Gültekin et al. 2017) and is reported at a frequency of 0.00023 in the East Asian population of the Genome Aggregation Database. Based on the collective evidence, the p.Phe710del variant is classified as pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000128553	SCV001587946	pathogenic	Glycogen storage disease, type V	2023-12-25	criteria provided, single submitter	clinical testing	This variant, c.2128_2130del, results in the deletion of 1 amino acid(s) of the PYGM protein (p.Phe710del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs527236147, gnomAD 0.02%). This variant has been observed in individuals with PYGM-related conditions (PMID: 7664468, 7951211, 8279469, 25045239, 28967462, 31320798). It has also been observed to segregate with disease in related individuals. This variant is also known as Phe708del and Phe709del. ClinVar contains an entry for this variant (Variation ID: 139609). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000128553	SCV002018991	likely pathogenic	Glycogen storage disease, type V	2020-08-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000128553	SCV002103786	pathogenic	Glycogen storage disease, type V	2022-02-02	criteria provided, single submitter	clinical testing	Variant summary: PYGM c.2128_2130delTTC (p.Phe710del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 1.2e-05 in 251490 control chromosomes. c.2128_2130delTTC has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type V (example, Sugie_1995, Park_2014, Ugur_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Sugie_1995). The most pronounced variant effect results in <5% of normal muscle myophosphorylase enzyme activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000128553	SCV004207299	pathogenic	Glycogen storage disease, type V	2022-12-20	criteria provided, single submitter	clinical testing
GeneReviews	RCV000128553	SCV000172200	not provided	Glycogen storage disease, type V		no assertion provided	literature only
Natera, Inc.	RCV000128553	SCV002092311	pathogenic	Glycogen storage disease, type V	2020-07-31	no assertion criteria provided	clinical testing