rs372731424
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP2PP3_Strong
The NM_000257.4(MYH7):āc.976G>Cā(p.Ala326Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,828 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A326T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.976G>C | p.Ala326Pro | missense_variant | 11/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.976G>C | p.Ala326Pro | missense_variant | 10/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.976G>C | p.Ala326Pro | missense_variant | 11/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251204Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135766
GnomAD4 exome AF: 0.000112 AC: 164AN: 1461664Hom.: 0 Cov.: 32 AF XY: 0.000128 AC XY: 93AN XY: 727128
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 27, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 05, 2019 | The p.Ala326Pro variant has been reported in 3 individuals with HCM (Michels 2009, D'Argenio 2014, LMM data). It has been identified in 19/126594 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs372731424). Clinvar: VUS (GeneDx, Invitae, CSER). Furthermore, alanine (Ala) at position 326 is not conserved in mammals or evolutionarily distant species, and the change to proline (Pro) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, due to conflicting data, the clinical significance of the p.Ala326Pro variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2018 | The A326P variant of uncertain significance in the MYH7 gene has been reported in association with HCM (Michels et al., 2009; D'Argenio et al, 2014; Homburger et al., 2016; Walsh et al., 2017). Michels et al. (2009) identified A326P in two unrelated probands with HCM as well as in two asymptomatic relatives, who had mild evidence of HCM upon clinical evaluation. A326P was also identified in an individual diagnosed with HCM shortly after birth, who harbored additional variants in the MYH7 and INS-IGF2 genes (D'Argenio et al, 2014). The A326P variant was inherited from the proband's clinically unaffected father (D'Argenio et al, 2014). This variant has also been identified, both independently and in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx; segregation data are limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members.The A326P variant is observed in 19/126,594 (0.015%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). A326P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this variant is located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018). However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 08, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 20, 2023 | This missense variant replaces alanine with proline at codon 326 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 19666645, 24183960, 27247418, 27476098, 27532257, 30696458, 31323898, 32369506, 33495597, 37466024) and in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). A family member of one proband was a healthy carrier (PMID: 24183960). This variant has also been identified in 25/282608 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 | Invitae | Oct 07, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 326 of the MYH7 protein (p.Ala326Pro). This variant is present in population databases (rs372731424, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19666645, 24183960, 27247418, 27532257, 31513939). ClinVar contains an entry for this variant (Variation ID: 43117). 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. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
Hypertrophic cardiomyopathy 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Dec 01, 2021 | - - |
Myosin storage myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 06, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | Low GERP score may suggest that this variant may belong in a lower pathogenicity class - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 06, 2021 | The c.976G>C (p.A326P) alteration is located in exon 11 (coding exon 9) of the MYH7 gene. This alteration results from a G to C substitution at nucleotide position 976, causing the alanine (A) at amino acid position 326 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at