ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2320G>A (p.Ala774Thr) (rs368104687)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035486 SCV000059135 uncertain significance not specified 2011-12-13 criteria provided, single submitter clinical testing The Ala774Thr variant (MYBPC3) has been reported in an individual with DCM and w as absent from 100 healthy control individuals. No clinical, details on this pa tient are available (Knueppel 2010, abstract only. diss/receive/FUDISS_thesis_000000002309?lang=en). This variant has been identif ied in 1 individual with HCM out of >4000 Caucasian chromosomes tested by our la boratory and was absent from 416 Caucasian and 374 Black control chromosomes (LM M unpublished data). This low frequency and absence in controls supports a path ogenic role. However, alanine (Ala) at position 774 is not well conserved in evo lution (1 mammalian species and lower species carry a proline), raising the poss ibility that a change at this position might be tolerated. Computational tools ( AlignGVGD, PolyPhen2, and SIFT) also predict that a change to threonine (Thr) wo uld not impact the protein, though their accuracy is unknown. In summary, curren tly available data fro this variant is inconclusive and additional studies are n eed to determine its clinical significance.
CSER_CC_NCGL; University of Washington Medical Center RCV000148678 SCV000190402 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000766349 SCV000208087 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing The Ala774Thr variant of uncertain significance in the MYBPC3 gene has been reported in association with cardiomyopathy (Knuppel et al., 2006; Maron et al., 2012). Knuppel et al. (2006) observed Ala774Thr in a patient with dilated cardiomyopathy (DCM); however, additional family member testing suggested that this variant may not be fully penetrant. This study did not observe Ala774Thr in 200 control chromosomes. Maron et al. (2012) reported Ala774Thr in a 18 year old male patient with HCM and a family history of sudden cardiac death. In addition, this variant has previously been reported in one other unrelated individual who was referred for DCM genetic testing at GeneDx and was classified in ClinVar as a variant of uncertain significance by another clinical laboratory (Landrum et al., 2014). Other missense changes at neighboring residues (Asp770Asn, Val771Met, Val771Ala) have been reported in HGMD in association with HCM (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Furthermore, Ala774Thr was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000415662 SCV000493758 uncertain significance Left ventricular noncompaction 10 2015-08-13 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000415709 SCV000493759 uncertain significance Familial hypertrophic cardiomyopathy 4 2015-08-13 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770335 SCV000901769 uncertain significance Cardiomyopathy 2016-06-01 criteria provided, single submitter clinical testing

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