Submissions for variant NM_021971.4(GMPPB):c.656T>C (p.Ile219Thr)

gnomAD frequency: 0.00004  dbSNP: rs761714818

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698360	SCV000827020	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14; Autosomal recessive limb-girdle muscular dystrophy type 2T	2024-10-22	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 219 of the GMPPB protein (p.Ile219Thr). This variant is present in population databases (rs761714818, gnomAD 0.01%). This missense change has been observed in individuals with alpha-dystroglycanopathy and congenital muscular dystrophy (PMID: 24780531, 26133662, 26310427; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 575991). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GMPPB protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814219	SCV001755298	likely pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001784331	SCV002018487	likely pathogenic	not provided	2020-09-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001784331	SCV002549175	pathogenic	not provided	2023-02-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with decreased enzymatic activity as compared to wild type (Liu et al., 2021); 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; This variant is associated with the following publications: (PMID: 24780531, 26133662, 30684953, 26310427, 30257713, 34758253, 35006422)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004547864	SCV003923045	likely pathogenic	GMPPB-related disorder	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: GMPPB c.656T>C (p.Ile219Thr) results in a non-conservative amino acid change located in the Nucleotidyl transferase domain (IPR005835) of 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 6.4e-05 in 251086 control chromosomes. This frequency does not allow conclusions about variant significance. c.656T>C has been reported in the literature as a compound heterzygous genotype in individuals affected with features of GMPPB-Related Disorders such as alpha-dystroglycanopathy, congenital muscular dystrophy, brain abnormalities and generalized epilepsy (example, PMID: 26133662, 26310427, 35006422, 24780531, 28688748). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 35006422). The most pronounced variant effect results in 40% of normal GDP-mannose pyrophosphorylase B (GMPPB) activity in-vitro. Four 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 likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001784331	SCV005092196	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	GMPPB: PM3:Very Strong, PM2, PP1, PS3:Supporting
Genomics England Pilot Project, Genomics England	RCV001542746	SCV001760127	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14		no assertion criteria provided	clinical testing