ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.821+1G>C

dbSNP: rs397516073
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000211831 SCV000205432 pathogenic Hypertrophic cardiomyopathy 2013-04-21 criteria provided, single submitter clinical testing The 821+1G>C variant in MYBPC3 has not been reported in individuals with cardiom yopathy and data from large population studies is insufficient to assess the fre quency of this variant. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leadin g to an abnormal or absent protein. Splicing and other truncating variants in MY BPC3 are established as pathogenic for HCM. In addition, other variants impactin g this splice site have been reported in individuals with HCM (821+1G>A, 821+2T> C, 821+5G>A; Carrier 1997, Niimura 1998, Flavigny 1999, Maron 2001, Flavigny 200 3, Richard 2003, Van Driest 2004, LMM unpublished data). In summary, this varian t meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/L MM) based upon the predicted impact of the variant.
Ambry Genetics RCV002426752 SCV002678280 pathogenic Cardiovascular phenotype 2020-11-06 criteria provided, single submitter clinical testing The c.821+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 7 of the MYBPC3 gene. This variant has been reported in a hypertrophic cardiomyopathy (HCM) genetic testing cohort; however, clinical details were limited (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 02;19:192-203). Another alteration impacting the same donor site (c.821+1G>A) has been described in multiple families with HCM and demonstrated segregation with disease; furthermore, mRNA analysis showed exon skipping resulting in abnormal transcripts (Niimura H et al. N Engl J Med. 1998 Apr;338:1248-57; Erdmann J et al. J Am Coll Cardiol. 2001 Aug;38:322-30). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000211831 SCV003439703 pathogenic Hypertrophic cardiomyopathy 2021-12-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 7 or exons 7 and 8 and introduces a premature termination codon (PMID: 11499719). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 178946). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9562578, 11499718, 11499719, 25611685, 27532257). 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 affects a donor splice site in intron 7 of the MYBPC3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.

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