ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.2623C>G (p.Pro875Ala)

dbSNP: rs201148948
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001324581 SCV001515540 uncertain significance Hyperkalemic periodic paralysis 2023-11-10 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 875 of the SCN4A protein (p.Pro875Ala). This variant is present in population databases (rs201148948, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1024403). 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 not expected to disrupt SCN4A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002546114 SCV003578112 uncertain significance Inborn genetic diseases 2021-09-01 criteria provided, single submitter clinical testing The c.2623C>G (p.P875A) alteration is located in exon 14 (coding exon 14) of the SCN4A gene. This alteration results from a C to G substitution at nucleotide position 2623, causing the proline (P) at amino acid position 875 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV003135979 SCV003818671 uncertain significance not provided 2019-02-27 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV004789525 SCV005398429 uncertain significance SCN4A-related myopathy, autosomal recessive 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Functional studies of missense variants have demonstrated both a loss and gain of protein function, even for the same phenotype (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance in congential myasthenic syndrome have been reported (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Some individuals carrying pathogenic variants do not present with a typical clinical phenotype, however they do have detectable signs of myotonia on EMG (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to alanine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 (11 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (267 heterozygotes, 1 homozygote). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated sodium ion transport-associated domain (NCBI, PDB). (I) 0710 - Another missense variant comparable to the one identified in this case has limited previous evidence for being benign. An alternative change to serine at the same residue has previously been classified as benign and likely benign (ClinVar, LOVD). (SB) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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