ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5882C>T (p.Pro1961Leu) (rs199473638)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620208 SCV000735155 likely benign Cardiovascular phenotype 2018-02-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058813 SCV000090333 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:19841300;PMID:20129283).
Color RCV000777978 SCV000914083 likely benign Arrhythmia 2018-04-16 criteria provided, single submitter clinical testing
GeneDx RCV000058813 SCV000235553 uncertain significance not provided 2016-10-31 criteria provided, single submitter clinical testing Kapa et al. (2009) reported P1962L as a rare variant in one of 1,300 unaffected control individuals in their LQTS study. However, the P1962L variant was not observed with any significant frequency in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, missense mutations in nearby residues (E1954K, R1958Q) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, although the P1962L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties; this substitution occurs at a position that is not conserved across species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV000638779 SCV000760327 likely benign Brugada syndrome 2017-12-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041634 SCV000065330 uncertain significance not specified 2012-10-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Pro1962Leu vari ant in SCN5A has not been previously reported by our laboratory. It has been ide ntified in 1/2600 control chromosomes (Kapa 2009) and in 3/8386 European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p:// Proline (Pro) at position 1962 is not conserved in mammals (maramoset has a Leucine (Leu; this variant) at this position) sugge sting that this variant may be tolerated. Additional computational analyses (bio chemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide s trong support for or against an impact to the protein. In summary, the frequency of this variant along with its presence in another primate supports that it may be benign, though additional studies are needed to fully assess its clinical si gnificance.

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