Submissions for variant NM_000256.3(MYBPC3):c.3535G>A (p.Glu1179Lys)

gnomAD frequency: 0.00036  dbSNP: rs199669878

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172003	SCV000050985	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035594	SCV000059245	likely benign	not specified	2019-09-24	criteria provided, single submitter	clinical testing	The p.Glu1179Lys variant in MYBPC3 is classified as likely benign because it has been identified in 0.19% (20/10318) of Ashkenazi Jewish and 0.13% (40/30546) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been identified in affected individuals (Brion 2009, Rodriquez-Garcia 2010, Kassem 2013, LMM data), the associated phenotypes are variable (including HCM, DCM, and SIDS), and some of these individuals carried variants in other genes sufficient to explain their disease. ACMG/AMP Criteria applied: BA1, PS4_Supporting.
GeneDx	RCV000172003	SCV000208177	likely benign	not provided	2020-11-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20433692, 25351510, 28771489, 22361390, 22563033, 23233322, 26914223, 22958901, 23861362, 24503780, 28679633, 26367797, no PMID, 28843747, 30972196, 30847666, 31980526)
Invitae	RCV001079285	SCV000284242	likely benign	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000035594	SCV000747992	uncertain significance	not specified	2017-05-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000509102	SCV001138286	benign	Hypertrophic cardiomyopathy 4	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001104836	SCV001261729	benign	Left ventricular noncompaction 10	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000509102	SCV001261730	uncertain significance	Hypertrophic cardiomyopathy 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171126	SCV001333806	likely benign	Cardiomyopathy	2022-11-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171126	SCV001357598	likely benign	Cardiomyopathy	2018-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035594	SCV001372387	likely benign	not specified	2020-06-24	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.3535G>A (p.Glu1179Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 247566 control chromosomes, predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3535G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Rodriguez-Garcia_2010, Kassem_2013, Garcia-Molina_2019), Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (Choung_2017) and Sudden Infant Death (SID) syndrome (Brion_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=4) or uncertain significance (n=6). Two of the ClinVar submitters mention co-occurrences with other pathogenic variants in patients carrying this variant without providing details. Based on the evidence outlined above, the variant was classified as likely benign.
Genetics and Genomics Program, Sidra Medicine	RCV001293111	SCV001434101	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000172003	SCV002544562	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336113	SCV002619090	likely benign	Cardiovascular phenotype	2021-12-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000172003	SCV000280263	likely benign	not provided	2016-11-04	no assertion criteria provided	provider interpretation	Based on this variant's presence in individuals with another disease-causing variant, and the frequency of this variant in the general population, including individuals of Ashkenazi Jewish descent (this patient's ethnicity), we classify this variant as likely benign and do not feel it is suitable for testing family members ("predictive genetic testing"). In total the variant has been seen in at least 12 seemingly unrelated cases of cardiac disease, mostly cardiomyopathy (not including the patient). However many of these individuals had another variant and, in addition, p.Glu1179Lys has also been observed at a higher than expected frequency in individuals from the general population. There is no segregation data available. ClinVar submissions include: variant of uncertain significance (LMM, GeneDx, CHEO, ClinSeq) and likely benign (Invitae). GeneDx notes that they have identified this variant in two other unrelated individuals tested for HCM in their lab (one had a disease-causing variant in another gene (not our case)) and one individual they tested for DCM (who also had a disease causing variant in another gene (could be our case, unclear at this time)). GeneDx identified this variant in 2 unaffected siblings of the proband. Segregation data is not available to date. LMM has identified this variant in 4 individuals with HCM, 2 with DCM and one individual with left ventricular dilation. Two of these individuals had variants in other genes that were sufficient to explain their disease. Per their report, "Glutamic acid (Glu) at position 1179 is not conserved in evolutionarily distant species and the change to Lysine (Lys) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011)." LMM's ClinVar submission notes a classification of variant of uncertain significance (as of March 25th, 2015). The entry notes LMM "has detected this variant in 4 individuals with HCM, 1 individual with LV dilatation, and in 1 individual with DCM." They do not note whether these individuals had other variants. Presumably the individual with left ventricular dilatation is the same case reported in Pugh et al (2014). We have seen p.Glu1179Lys in another patient with HCM, who had only this one variant. We have also seen the variant in a 1yo girl with non-compaction and dilated cardiomyopathy. She also had a variant in DES (not classified by us yet). Rodriguez-Garcia et al (2010) reported the variant in a patient with HCM from their Spanish cohort. Of note, they only reported on MYBPC3 in that paper so it is not known whether the patient had variants in other HCM genes. It appears that Brion et al (2012) may have observed the variant in a SIDS case (with a normal heart), though unfortunately the paper is not available to us. Kassem et al (2012) reported the variant in one of 192 Egyptian patients with HCM. MYBPC3, MYH7, and TNNT2 were sequenced and p.Glu1179Lys was the only variant that patient harbored in those genes. LMM reported a patient with this variant in their DCM series (Pugh et al 2014). The patient was a 32yo Caucasian female with left ventricular dilation and regional wall abnormalities. She underwent a 46 gene cardiomyopathy panel and carried multiple variants of uncertain significance in addition to this one (including variants in ABCC9, CASQ2, DSP). Sabater-Molina et al 2013 note they found this variant in a European cohort (mostly Spanish, but authors not overlapping with Rodriguez-Garcia et al 2010) with various inherited cardiovascular diseases. Unfortunately it is not noted which condition this was observed with, though patients with HCM made up roughly half the cohort. Maron et al (2012) report a "G+LVH-" patient with this variant who has a maximal left ventricular wall thickness of 1.0 cm and had three crypts on imaging. The substitution is chemically conservative and in silico analyses with SIFT and PolyPhen predict the variant to be benign. LMM's ClinVar assertion notes the variant was "predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011)." The glutamic acid at codon 1179 is not conserved in mammals. Per the GeneDx report (citing HGMD) other variants in nearby codons have been reported in association with disease (p.Tyr1172Cys, p.Thr1184Asn, p.Leu1187Arg). The glu at codon 1179 is conserved across species. This variant has been seen in 117 out of 140,595 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino descent. The data includes 126,216 exomes and 15,137 genomes (as of October 21, 2016). Specifically, this variant is present in 20 out of 5,066 individuals of Ashkenazi Jewish descent, 40 out of 15,422 individuals of South Asian descent, 19 out of 18,187 individuals of Latino descent, 35 out of 62,939 individuals of European (Non-Finnish) descent and 2 out of 12,849 individuals of African descent.
GenomeConnect, ClinGen	RCV000509102	SCV000607141	not provided	Hypertrophic cardiomyopathy 4		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000172003	SCV001552868	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYBPC3 p.Glu1179Lys variant was identified in 3 of 1956 proband chromosomes (frequency: 0.0015) from individuals or families with hypertrophic and dilated cardiomyopathies (Pugh_2014_PMID:24503780; Rodríguez-García_2010_PMID:20433692; Kassem_2012_PMID:23233322). The variant was also identified in dbSNP (ID: rs199669878), ClinVar (classified as a VUS by four laboratories and as likely benign by two laboratories) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 115 of 278922 chromosomes at a frequency of 0.000412 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 20 of 10318 chromosomes (freq: 0.001938), South Asian in 40 of 30546 chromosomes (freq: 0.00131), Latino in 16 of 35212 chromosomes (freq: 0.000454), Other in 2 of 7090 chromosomes (freq: 0.000282), European (non-Finnish) in 35 of 127334 chromosomes (freq: 0.000275) and African in 2 of 24006 chromosomes (freq: 0.000083), while the variant was not observed in the East Asian and European (Finnish) populations. The E1179K variant was identified in 1/140 cases of sudden infant death syndrome (Brion_2009). The p.Glu1179 residue is conserved in mammals and 3 of 4 computational analyses (SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however this information is not enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.