rs200751434
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_002471.4(MYH6):c.4772A>G(p.Asn1591Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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MYH6 | NM_002471.4 | c.4772A>G | p.Asn1591Ser | missense_variant | Exon 33 of 39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251488Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135916
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461890Hom.: 0 Cov.: 69 AF XY: 0.0000330 AC XY: 24AN XY: 727248
GnomAD4 genome AF: 0.000223 AC: 34AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74468
ClinVar
Submissions by phenotype
not provided Uncertain:5
The MYH6 c.4772A>G; p.Asn1591Ser variant (rs200751434) is reported in the literature in an infant with hypertrophic cardiomyopathy that also carried a pathogenic PTPN11 variant (Aljeaid 2019). Additionally, in testing performed at ARUP Laboratories, the MYH6 p.Asn1591Ser variant has been detected in an individual with left ventricular noncompaction who carried a pathogenic variant in a different gene. The p.Asn1591Ser variant is found in the African population with an overall allele frequency of 0.03% (7/24956 alleles) in the Genome Aggregation Database. The asparagine at codon 1591 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Asn1591Ser variant is uncertain at this time. References: Aljeaid D et al. Prevalence of pathogenic and likely pathogenic variants in the RASopathy genes in patients who have had panel testing for cardiomyopathy. Am J Med Genet A. 2019 Apr;179(4):608-614. -
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Reported in a 9-month-old male presenting with HCM who also harbored the T468M pathogenic variant in the PTPN11 gene (PMID: 30762279); Reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia or family history of sudden cardiac death, who underwent exome sequencing; however, a follow-up cardiac evaluation was not described (PMID: 23861362); 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: 30762279, 23861362) -
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not specified Uncertain:1
The Asn1591Ser variant in MYH6 has been identified in 1/8600 European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/ as well as an additional 1/1323 European chromosomes (dbSNP rs200751434). Note that these could represent presymptomatic individual s. Computational analyses (biochemical amino acid properties, conservation, Alig nGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impa ct to the protein. Additional information is needed to fully assess the clinical significance of this variant. -
Hypertrophic cardiomyopathy 14 Uncertain:1
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1591 of the MYH6 protein (p.Asn1591Ser). This variant is present in population databases (rs200751434, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30762279). ClinVar contains an entry for this variant (Variation ID: 44519). 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 not expected to disrupt MYH6 protein function with a negative predictive value of 80%. 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. -
Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at