ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.4765G>A (p.Val1589Met)

dbSNP: rs121908548
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000518064 SCV000615103 pathogenic not provided 2021-10-19 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to impaired SCN4A channel activity (PMID: 7965854).
Labcorp Genetics (formerly Invitae), Labcorp RCV000800365 SCV000940077 pathogenic Familial hyperkalemic periodic paralysis 2023-09-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN4A function (PMID: 11744749). 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 SCN4A protein function. ClinVar contains an entry for this variant (Variation ID: 5905). This missense change has been observed in individuals with paramyotonia congenita (PMID: 8242056, 9771789, 18166706, 23771340, 23810313, 25755818). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1589 of the SCN4A protein (p.Val1589Met).
CeGaT Center for Human Genetics Tuebingen RCV000518064 SCV001501684 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000518064 SCV001824082 pathogenic not provided 2024-04-22 criteria provided, single submitter clinical testing Multiple in vitro and in vivo functional studies show that V1589M alters properties of channel inactivation, resulting in faster channel recovery after inactivation. Rapid re-opening of sodium channels most likely underlies the hyperexcitability associated with sodium channel myotonia (PMID: 1668369, 7965854, 11744749, 28877545); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28378410, 11744749, 8242056, 18166706, 29050397, 21664816, 7965854, 28877545, 1668369, 9771789, 27415035, 25755818, 33573884, 23771340, 36796140, 21387378, 27486940, 33325393, 22016737, 16624558, 32670189, 36782059, 23810313)
Revvity Omics, Revvity RCV000518064 SCV002020025 pathogenic not provided 2022-08-30 criteria provided, single submitter clinical testing
DASA RCV001849259 SCV002107110 pathogenic Hypokalemic periodic paralysis, type 2 2022-03-05 criteria provided, single submitter clinical testing Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11744749; 7965854; 8242056) - PS3_moderate.The c.4765G>A;p.(Val1589Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5905; PMID: 25755818; PMID: 9771789; PMID: 23810313; PMID:23771340; PMID: 18166706; PMID: 16624558) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ion_trans; PKD_channel) - PM1. This variant is not present in population databases (rs121908548- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 25755818; 16624558; 9771789) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
MGZ Medical Genetics Center RCV000006268 SCV002580238 pathogenic Paramyotonia congenita of Von Eulenburg 2021-09-10 criteria provided, single submitter clinical testing
OMIM RCV000006267 SCV000026449 pathogenic Potassium-aggravated myotonia 1998-10-01 no assertion criteria provided literature only
OMIM RCV000006268 SCV000026450 pathogenic Paramyotonia congenita of Von Eulenburg 1998-10-01 no assertion criteria provided literature only

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