14-23415766-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000257.4(MYH7):c.5020G>A(p.Val1674Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1674L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5020G>A | p.Val1674Met | missense_variant | 35/40 | ENST00000355349.4 | |
MHRT | NR_126491.1 | n.198C>T | non_coding_transcript_exon_variant | 2/6 | |||
MYH7 | NM_001407004.1 | c.5020G>A | p.Val1674Met | missense_variant | 34/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.5020G>A | p.Val1674Met | missense_variant | 35/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251412Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135884
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461894Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8AN XY: 727248
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 06, 2023 | This missense variant replaces valine with methionine at codon 1674 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 25611685). This variant has been identified in 3/251412 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 29, 2023 | This missense variant replaces valine with methionine at codon 1674 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 25611685). This variant has been identified in 3/251412 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. - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jan 05, 2024 | This sequence change in MYH7 is predicted to replace valine with methionine at codon 1674, p.(Val1674Met). The valine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the myosin tail domain. There is a small physicochemical difference between valine and methionine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.002% (2/91,086 alleles) in the South Asian population, which is consistent with hypertrophic cardiomyopathy. This variant has been reported in at least one individual with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been observed in an individual with a pathogenic variant in MYBPC3 (Royal Melbourne Hospital). Computational evidence is uninformative for the missense substitution (REVEL = 0.498). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1674 of the MYH7 protein (p.Val1674Met). This variant is present in population databases (rs397516235, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43052). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 14, 2012 | The Val1674Met variant in MYH7 has not been reported in the literature, but has been identified in 1 individual with HCM (this individual) out of >3600 probands (>2200 Caucasian) tested by our laboratory. In addition, this variant has not b een identified in large and broad populations (European and African American) se quenced by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS) . While this low frequency supports a pathogenic role, the ethnicity of this ind ividual was not specified and it remains possible that this variant is common in other populations. Valine (Val) at position 1674 is highly conserved in mammal and across evolutionarily distant species, though the change to methionine (Met) was predicted to be benign using a computational tool, which was validated by o ur laboratory using a set of cardiomyopathy variants with well-established clini cal significance (benign predictions are estimated to be correct 89% of the time , Jordan 2011). Additional studies are needed to fully assess the clinical signi ficance of this variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at