Submissions for variant NM_000257.4(MYH7):c.4864C>T (p.Leu1622Phe)

gnomAD frequency: 0.00001  dbSNP: rs397516231

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035936	SCV000059587	uncertain significance	not specified	2014-01-20	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766464	SCV000208610	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	Identified in patients with HCM in published literature (PMID: 27247418, 27532257, 37652022); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27247418, 37652022, 34542152, 27532257)
Ambry Genetics	RCV000620735	SCV000740071	uncertain significance	Cardiovascular phenotype	2016-11-23	criteria provided, single submitter	clinical testing	The c.4864C>T (p.L1622F) alteration is located in exon 34 (coding exon 32) of the MYH7 gene. This alteration results from a C to T substitution at nucleotide position 4864, causing the leucine (L) at amino acid position 1622 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001039843	SCV001203392	uncertain significance	Hypertrophic cardiomyopathy	2024-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1622 of the MYH7 protein (p.Leu1622Phe). This variant is present in population databases (rs397516231, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 43042). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001185538	SCV001351782	uncertain significance	Cardiomyopathy	2021-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1622 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 30297972). This variant has been identified in 1/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.