Submissions for variant NM_000432.4(MYL2):c.51_61del (p.Phe18fs)

dbSNP: rs754744244

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001214509	SCV001386192	uncertain significance	Hypertrophic cardiomyopathy 10	2024-11-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe18Argfs*9) in the MYL2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYL2 cause disease. This variant is present in population databases (rs754744244, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYL2-related conditions. ClinVar contains an entry for this variant (Variation ID: 944169). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV001780132	SCV002017852	likely pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001780132	SCV005419473	uncertain significance	not provided	2024-05-31	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease
Neuberg Centre For Genomic Medicine, NCGM	RCV005208158	SCV005849422	likely pathogenic	Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy		criteria provided, single submitter	clinical testing	The observed frameshift variant c.51_61del(p.Phe18ArgfsTer9) in MYL2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/Uncertain Significance. This variant causes a frameshift starting with codon Phenylalanine 18, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Phe18ArgfsTer9. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing(Manivannan SN et.al., 2020). For these reasons, this variant has been classified as Likely Pathogenic.