Submissions for variant NM_000256.3(MYBPC3):c.481C>A (p.Pro161Thr)

gnomAD frequency: 0.00001  dbSNP: rs397516053

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035634	SCV000059285	uncertain significance	not specified	2017-08-30	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro161Thr variant in MYBPC3 has been reported in 4 individuals with HCM (Kapplinger 2014, LMM data). This variant has been reported in ClinVar (Variant ID 42759). This v ariant has been identified in 1/68078 European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org). Computational predicti on tools and conservation analysis suggest that the p.Pro161Thr variant may impa ct the protein, though this information is not predictive enough to determine pa thogenicity. In summary, while there is some suspicion for a pathogenic role, th e clinical significance of the p.Pro161Thr variant is uncertain.
GeneDx	RCV000766309	SCV000208219	uncertain significance	not provided	2022-03-14	criteria provided, single submitter	clinical testing	Reported in individuals diagnosed with HCM or referred for HCM genetic testing, although patient-specific details were not provided (Bos et al., 2014; Kapplinger et al., 2014; Murphy et al., 2016; Walsh et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26914223, 24510615, 24793961, 27532257)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228800	SCV000284246	uncertain significance	Hypertrophic cardiomyopathy	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 161 of the MYBPC3 protein (p.Pro161Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24510615, 24793961, 27532257, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 42759). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Pro161 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 14563344), which suggests that this may be a clinically significant amino acid residue. 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	RCV000244834	SCV000319960	likely pathogenic	Cardiovascular phenotype	2025-02-10	criteria provided, single submitter	clinical testing	The p.P161T variant (also known as c.481C>A), located in coding exon 4 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 481. The proline at codon 161 is replaced by threonine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Bos JM et al. Mayo Clin Proc, 2014 Jun;89:727-37; Walsh R et al. Genet Med, 2017 02;19:192-203; Tadros R et al. Nat Genet, 2021 02;53:128-134; Harper AR et al. Nat Genet, 2021 02;53:135-142). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000244834	SCV000747958	pathogenic	Cardiovascular phenotype	2025-01-28	criteria provided, single submitter	clinical testing	PS4, PP1_strong, PM2, PM5, PP3
All of Us Research Program, National Institutes of Health	RCV000228800	SCV004834774	uncertain significance	Hypertrophic cardiomyopathy	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 161 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 2 individuals affected with hypertrophic cardiomyopathy (PMID: 26914223, 27532257). This variant has been identified in 1/172084 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.