Submissions for variant NM_019023.5(PRMT7):c.1056-1G>T

gnomAD frequency: 0.00007  dbSNP: rs201824659

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001551441	SCV001771952	pathogenic	not provided	2025-01-31	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22527104, 30513135, 30006058, 28902392, 31589614, 36399134, 26437029)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001551441	SCV002011542	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000256436	SCV002024747	likely pathogenic	Short stature-brachydactyly-obesity-global developmental delay syndrome	2019-12-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001551441	SCV002242678	pathogenic	not provided	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 of the PRMT7 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PRMT7 are known to be pathogenic (PMID: 26437029, 27718516). This variant is present in population databases (rs201824659, ExAC 0.01%). Disruption of this splice site has been observed in individual(s) with intellectual disability, obesity, and shortened phalanges (PMID: 2643702). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 266024). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000256436	SCV004029593	pathogenic	Short stature-brachydactyly-obesity-global developmental delay syndrome	2023-07-12	criteria provided, single submitter	clinical testing	Variant summary: PRMT7 c.1056-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site. Two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.8e-05 in 250392 control chromosomes. c.1056-1G>T has been reported in the literature in multiple individuals affected with Short Stature, Brachydactyly, Intellectual Developmental Disability, And Seizures (Cali_2023, Akawi_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26437029, 36399134). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=5) and benign (n=1) . Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000256436	SCV000323185	pathogenic	Short stature-brachydactyly-obesity-global developmental delay syndrome	2020-07-03	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000256436	SCV000840127	not provided	Short stature-brachydactyly-obesity-global developmental delay syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001264712	SCV001442895	pathogenic	Neurodevelopmental abnormality	2020-06-04	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754369	SCV005355734	pathogenic	PRMT7-related disorder	2024-04-30	no assertion criteria provided	clinical testing	The PRMT7 c.1056-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant in the homozygous or along with a second allele in this gene has been reported multiple individuals with pseudohypoparathyroidism (Akawi et al. 2015. PubMed ID: 26437029; Table S1, Cali et al. 2022. PubMed ID: 36399134). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in PRMT7 are expected to be pathogenic. This variant is interpreted as pathogenic.