Submissions for variant NM_000258.3(MYL3):c.532G>A (p.Asp178Asn) (rs145520567)

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Total submissions: 7

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000036031	SCV000059683	uncertain significance	not specified	2018-05-21	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Asp178Asn var iant in MYL3 has been reported in 3 individuals with hypertrophic cardiomyopathy (Weissler-Snir 2017, LMM Data), but has also been identified in 0.14% (44/30782 ) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org/; dbSNP rs145520567). This variant is also reported in ClinVar (Variation ID 43128). Computational prediction tools and conservation a nalysis suggest that the p.Asp178Asn variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, wh ile the clinical significance of the p.Asp178Asn variant is uncertain, its frequ ency in the general population suggests that it is more likely to be benign. ACM G/AMP Criteria applied: PP3, PS4_Supporting, BS1.
GeneDx	RCV000587491	SCV000208891	uncertain significance	not provided	2018-11-01	criteria provided, single submitter	clinical testing	The D178N variant of uncertain significance in the MYL3 gene has been reported in one individual from a cohort with clinically confirmed HCM, though patient-specific details were not provided (Weissler-Snir et al., 2017). Bick et al. (2012) reported D178N as a variant of uncertain significance in two patients in the Framingham and Jackson Heart Study cohorts. The D178N variant has been identified in several probands referred to GeneDx for HCM genetic testing; segregation data are currently uninformative. This variant is observed in 56/276934 (0.02%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the D178N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina	RCV000262754	SCV000444746	uncertain significance	Hypertrophic cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000262754	SCV000549162	likely benign	Hypertrophic cardiomyopathy	2019-12-31	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000587491	SCV000696365	likely benign	not provided	2016-01-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000769163	SCV000900538	uncertain significance	Cardiomyopathy	2016-08-03	criteria provided, single submitter	clinical testing
Color	RCV000769163	SCV000904646	likely benign	Cardiomyopathy	2019-11-17	criteria provided, single submitter	clinical testing

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