Submissions for variant NM_000256.3(MYBPC3):c.3362G>A (p.Arg1121His)

gnomAD frequency: 0.00001  dbSNP: rs397516018

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000035584	SCV000208393	likely benign	not specified	2017-02-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV001105975	SCV001262999	uncertain significance	Hypertrophic cardiomyopathy 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001105976	SCV001263000	benign	Left ventricular noncompaction 10	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV001176064	SCV001339897	likely benign	Cardiomyopathy	2020-12-23	criteria provided, single submitter	clinical testing
Invitae	RCV002054566	SCV002412558	likely benign	Hypertrophic cardiomyopathy	2022-10-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000786362	SCV003817158	uncertain significance	not provided	2020-11-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035584	SCV000059234	uncertain significance	not specified	2008-03-01	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786362	SCV000925158	uncertain significance	not provided	2016-09-01	no assertion criteria provided	provider interpretation	Genetic testing: The patient had genetic testing with the GeneDx laboratory with their comprehensive cardiomyopathy panel. The test included 76 genes associated with various hereditary cardiomyopathies: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3, BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL, NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43,TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Analysis included both sequencing and array-based comparative genome hybridization to look for duplications and deletions (excluding mitochondrial genes, FKTN, GATAD1) Results reported on October 13, 2016 showed that a variant was found (see report below): p.Arg1121His (c.3362G>A) in the MYBPC3 gene (NM_000256.3) Given a lack of case data we consider this variant a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has been reported twice in Clinvar. This change is a conservative amino acid substitution which is not likely to impact secondary protein structure as these residues share the same properties. In silico analysis with PolyPhen-2 predicts the variant to be benign (HumVar = 0.011). The Arg at codon 1121 is not well conserved across species (histadine is the natural amino acid at this position in elephants and cows). No other variant have been reported in cardiomyopathy patients at this position, but there have been pathogenic missense variants in areas near this variant (F1113I, V1115I, C1124R, V1125M). There are 13 individuals with variation at codon 1121 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 1, 2016). 11 individuals have the same p.Arg1121His change while 2 individuals have a p.Arg1121Cys. The average coverage at that site in ExAC is around 28x.