Submissions for variant NM_017739.4(POMGNT1):c.1814G>C (p.Arg605Pro)

dbSNP: rs267606962

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671290	SCV000796251	likely pathogenic	Muscle eye brain disease	2017-12-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824425	SCV000965323	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2022-10-23	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with muscular dystrophy-dystroglycanopathy (PMID: 19299310, 19679478, 23689641, 24731844). ClinVar contains an entry for this variant (Variation ID: 3998). 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) performed at Invitae indicates that this missense variant is expected to disrupt POMGNT1 protein function. This variant disrupts the p.Arg605 amino acid residue in POMGNT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21361872, 24731844). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs267606962, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 605 of the POMGNT1 protein (p.Arg605Pro).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268426	SCV001447357	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000004205	SCV002058674	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2022-01-03	criteria provided, single submitter	clinical testing	The variant observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.903, PP3_P). The varianthas been previously reported multiple times as pathogenic or likely pathogenic (ClinVar: VCV000003998). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000004205	SCV002576459	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2022-09-08	criteria provided, single submitter	clinical testing	This variant was identified as homozygous._x000D_ Criteria applied: PM5_STR, PM1, PM3, PM2_SUP, PP3
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002512740	SCV003761149	likely pathogenic	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The p.Arg605Pro variant in POMGNT1 has been reported in three individuals with muscular dystrophy-dystroglycanopathy (PMID: 19299310, 19679478), and has been identified in 0.01% (1/9970) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267606962). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#:3998) and has been interpreted as pathogenic by multiple labs. Of the three affected individuals, two were homozygotes, which increases the likelihood that the p.Arg605Pro variant is pathogenic (PMID: 19299310, 19679478). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg605His, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 33726816, 17154333/Variation ID: 56589). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PM3, PM5_Supporting, PP3, PM2 (Richards 2015).
Institute of Human Genetics, University of Leipzig Medical Center	RCV003322587	SCV004027830	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2023-06-28	criteria provided, single submitter	clinical testing	Criteria applied: PM5_STR,PM1,PM3,PM2_SUP,PP3
Baylor Genetics	RCV003322587	SCV004206031	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2021-12-01	criteria provided, single submitter	clinical testing
OMIM	RCV000004205	SCV000024371	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2009-05-26	no assertion criteria provided	literature only
Natera, Inc.	RCV000671290	SCV002089585	likely pathogenic	Muscle eye brain disease	2021-04-21	no assertion criteria provided	clinical testing