Submissions for variant NM_002461.3(MVD):c.70+5G>A

gnomAD frequency: 0.00306  dbSNP: rs200035262

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002291775	SCV002584221	pathogenic	not provided	2025-02-11	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30942823, 34426522, 16924058, 33491095, 31449901, 32767669, 33005717, 37726979, 37301908)
CeGaT Center for Human Genetics Tuebingen	RCV002291775	SCV004033509	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	MVD: PM2, PM3, PP3, PS3:Supporting, PS4:Supporting
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017873	SCV004847436	uncertain significance	Porokeratosis 7, multiple types	2024-02-16	criteria provided, single submitter	clinical testing	The c.70+5G>A variant in MVD has been reported in 17 heterozygous individuals with different types of porokeratosis, but only a small subset of these individuals had a second hit identified in the parakeratotic cells. This variant did segregate with disease in 2 affected relatives from 1 family (Atzmony 2019 PMID: 30942823, Atzmony 2020 PMID: 31449901, Jagle 2021 PMID: 33491095, Saleva-Stateva 2021 PMID: 32767669). This variant has also been identified in 0.41% (4826/1174726) of European (non-Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0) and in ClinVar (Variation ID 1344813). This variant is located in the 5' splice region and computational prediction tools suggest an impact on splicing. In vitro functional studies demonstrated reduced levels of the wildtype transcript, possibly as a result of degradation of the variant transcript by nonsense-mediated decay (NMD) (Atzmony 2019 PMID: 30942823). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PS3_Supporting.
Yale Center for Mendelian Genomics, Yale University	RCV001849815	SCV002106922	likely pathogenic	Linear porokeratosis	2020-08-22	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003923337	SCV004743730	likely benign	MVD-related disorder	2019-05-09	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).