ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3535G>A (p.Glu1179Lys) (rs199669878)

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Total submissions: 15
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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,Partners HealthCare 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 RCV000035594 SCV000208177 uncertain significance not specified 2016-10-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYBPC3 gene. The E1179K variant has previously been reported in association with HCM (Rodriguez-Garcia et al., 2010; Bick et al., 2012; Maron et al., 2012; Kassem et al., 2013) and sudden infant death syndrome (SIDS) (Brion et al., 2012). However, Rodriguez-Garcia et al. (2010) also identified this variant in two unaffected siblings of the proband. This variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx; however, segregation data is uninformative. E1179K has been classified in ClinVar as a variant of uncertain significance and as a likely benign variant by other clinical laboratories (ClinVar SCV000059245.4, SCV000284242.1, SCV000280263.1, SCV000219817.1; Landrum et al., 2016). Nevertheless, the E1179K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and 2/3 in silico prediction programs predicts this variant is probably damaging to the protein structure/function. However, the Exome Aggregation Consortium (ExAC) and the NHLBI Exome Sequencing Project report E1179K was observed in 22/15,208 alleles from individuals of South Asian ancestry and 6/8,254 alleles from individuals of European ancestry, respectively, indicating it may be a rare benign variant in these populations.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV001079285 SCV000284242 likely benign Hypertrophic cardiomyopathy 2020-11-24 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 uncertain significance Familial hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000509102 SCV001261730 uncertain significance Familial 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 uncertain significance Cardiomyopathy 2018-10-09 criteria provided, single submitter clinical testing
Color Health, Inc 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
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 Familial 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.

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